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Clinical Cancer Research : An Official... Jan 2023Viral infections are a major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT). In the absence of safe and effective...
PURPOSE
Viral infections are a major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT). In the absence of safe and effective antiviral treatments, virus-specific T cells have emerged as a promising therapeutic option. Posoleucel is a multivirus-specific T-cell therapy for off-the-shelf use against six viral infections that commonly occur in allo-HCT recipients: adenovirus, BK virus (BKV), cytomegalovirus, Epstein-Barr virus, human herpes virus-6, and JC virus.
PATIENTS AND METHODS
We conducted an open-label, phase II trial to determine the feasibility and safety of posoleucel in allo-HCT recipients infected with one or more of these viruses. Infections were either unresponsive to or patients were unable to tolerate standard antiviral therapies. Fifty-eight adult and pediatric patients were enrolled and treated.
RESULTS
Posoleucel was well tolerated, with no cytokine release syndrome or other infusion-related toxicities; two patients (3.4%) developed Grade 2 and one patient (1.7%) Grade 3 GvHD during the trial. The overall response rate 6 weeks after the first posoleucel infusion was 95%, with a median plasma viral load reduction of 97%. Of the 12 patients who had two or more target viral infections identified at study entry, 10 (83%) had a clinical response for all evaluable viruses. Of the 23 patients treated for refractory BKV-associated hemorrhagic cystitis, 74% had resolution of symptoms and macroscopic hematuria by 6 weeks post-infusion.
CONCLUSIONS
In this open-label trial, treatment of refractory viral infections/disease in allo-HCT recipients with posoleucel was feasible, safe, and effective.
Topics: Adult; Child; Humans; Antiviral Agents; Cell- and Tissue-Based Therapy; Epstein-Barr Virus Infections; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; Virus Diseases
PubMed: 36628536
DOI: 10.1158/1078-0432.CCR-22-2415 -
Plastic and Reconstructive Surgery Jan 2018A number of textbooks, review articles, and case reports highlight the potential comorbidity of choanal atresia in craniosynostosis patients. However, the lack of a... (Review)
Review
A number of textbooks, review articles, and case reports highlight the potential comorbidity of choanal atresia in craniosynostosis patients. However, the lack of a precise definition of choanal atresia within the current craniosynostosis literature and widely varying methods of detection and diagnosis have produced uncertainty regarding the true coincidence of these conditions. The authors review the anatomy and embryologic basis of the human choanae, provide an overview of choanal atresia, and analyze the available literature that links choanal atresia and craniosynostosis. Review of over 50 case reports that describe patients diagnosed with both conditions reveals inconsistent descriptions of choanal atresia and limited use of definitive diagnostic methodologies. The authors further present preliminary analysis of three-dimensional medical head computed tomographic scans of children diagnosed with craniosynostosis syndromes (e.g., Apert, Pfeiffer, Muenke, and Crouzon) and typically developing children and, although finding no evidence of choanal atresia, report the potentially reduced nasal airway volumes in children diagnosed with Apert and Pfeiffer syndromes. A recent study of the Fgfr2c Crouzon/Pfeiffer syndrome mouse model similarly found a significant reduction in nasal airway volumes in littermates carrying this FGFR2 mutation relative to unaffected littermates, without detection of choanal atresia. The significant correlation between specific craniosynostosis syndromes and reduced nasal airway volume in mouse models for craniosynostosis and human pediatric patients indicates comorbidity of choanal and nasopharyngeal dysmorphologies and craniosynostosis conditions. Genetic, developmental, and epidemiologic sources of these interactions are areas particularly worthy of further research.
Topics: Abnormalities, Multiple; Animals; Choanal Atresia; Craniosynostoses; Genetic Markers; Humans; Mice; Mutation; Nasopharynx; Receptor, Fibroblast Growth Factor, Type 2; Syndrome
PubMed: 29280877
DOI: 10.1097/PRS.0000000000003928 -
The Journal of Clinical Endocrinology... Jul 2021
Topics: Humans; Insulin Resistance; Prediabetic State
PubMed: 33765140
DOI: 10.1210/clinem/dgab198 -
European Journal of Orthodontics May 2022To determine whether dental maturity (dental development) was delayed in patients with Muenke syndrome, Saethre-Chotzen syndrome, and TCF12-related craniosynostosis,...
OBJECTIVES
To determine whether dental maturity (dental development) was delayed in patients with Muenke syndrome, Saethre-Chotzen syndrome, and TCF12-related craniosynostosis, compared with a Dutch control group without syndromes.
MATERIALS AND METHODS
This study included 60 patients (38 patients with Muenke syndrome, 17 patients with Saethre-Chotzen syndrome, and 5 with TCF12-related craniosynostosis), aged 5.8-16.8 years that were treated at the Department of Oral Maxillofacial Surgery, Special Dental Care, and Orthodontics, in Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, the Netherlands. Dental age was calculated according to Demirjian's index of dental maturity. The control group included 451 children without a syndrome.
RESULTS
Compared with the control group, dental development was delayed by an average of one year in 5- to 8-year-old patients with Muenke syndrome (P = 0.007) and in 8- to 10-year-old patients with Saethre-Chotzen syndrome (P = 0.044), but not in patients with TCF12-related craniosynostosis.
CONCLUSIONS
Our results indicated that dental development was delayed by one year, on average, in patients with Muenke syndrome and Saethre-Chotzen syndrome, compared with a Dutch control group without syndromes.
IMPLICATIONS
Our findings have improved the understanding of dental development in patients with Muenke and Saethre-Chotzen syndrome. These results can provide guidance on whether the orthodontist needs to consider growth disturbances related to dental development.
Topics: Acrocephalosyndactylia; Basic Helix-Loop-Helix Transcription Factors; Child; Child, Preschool; Craniosynostoses; Humans; Netherlands; Syndrome
PubMed: 34424951
DOI: 10.1093/ejo/cjab056 -
Genes Oct 2022Objective: To report the clinical and radiographic findings and molecular etiology of the first monozygotic twins affected with Pfeiffer syndrome. Methods: Clinical and...
Objective: To report the clinical and radiographic findings and molecular etiology of the first monozygotic twins affected with Pfeiffer syndrome. Methods: Clinical and radiographic examination and whole exome sequencing were performed on two monozygotic twins with Pfeiffer syndrome. Results: An acceptor splice site mutation in FGFR2 (c.940-2A>G) was detected in both twins. The father and both twins shared the same haplotype, indicating that the mutant allele was from their father’s chromosome who suffered severe upper airway obstruction and subsequent obstructive sleep apnea. Hypertrophy of nasal turbinates appears to be a newly recognized finding of Pfeiffer syndrome. Increased intracranial pressure in both twins were corrected early by fronto-orbital advancement with skull expansion and open osteotomy, in order to prevent the more severe consequences of increased intracranial pressure, including hydrocephalus, the bulging of the anterior fontanelle, and the diastasis of suture. Conclusions: Both twins carried a FGFR2 mutation and were discordant for lambdoid synostosis. Midface hypoplasia, narrow nasal cavities, and hypertrophic nasal turbinates resulted in severe upper airway obstruction and subsequent obstructive sleep apnea in both twins. Hypertrophy of the nasal turbinates appears to be a newly recognized finding of Pfeiffer syndrome. Fronto-orbital advancement with skull expansion and open osteotomy was performed to treat increased intracranial pressure in both twins. This is the first report of monozygotic twins with Pfeiffer syndrome.
Topics: Humans; Acrocephalosyndactylia; Twins, Monozygotic; Sleep Apnea, Obstructive; Airway Obstruction; Hypertrophy
PubMed: 36292735
DOI: 10.3390/genes13101850 -
Movement Disorders Clinical Practice May 2022There is a close link between multiple movement disorders and gastrointestinal dysfunction. Gastrointestinal symptoms may precede the development of the neurologic... (Review)
Review
There is a close link between multiple movement disorders and gastrointestinal dysfunction. Gastrointestinal symptoms may precede the development of the neurologic syndrome or may arise following the neurologic presentation. This review will provide an overview of gastrointestinal accompaniments to several well-known as well as lesser known movement disorders. It will also highlight several disorders which may not be considered primary movement disorders but have an overlapping presentation of both gastrointestinal and movement abnormalities.
PubMed: 35586541
DOI: 10.1002/mdc3.13407 -
Frontiers in Genetics 2022The Crouzon syndrome mouse model carries a cysteine to tyrosine substitution at amino acid position 342 (Cys342Tyr; C342Y) in the fibroblast growth factor receptor 2...
The Crouzon syndrome mouse model carries a cysteine to tyrosine substitution at amino acid position 342 (Cys342Tyr; C342Y) in the fibroblast growth factor receptor 2 () gene equivalent to a mutation commonly associated with Crouzon and Pfeiffer syndromes in humans. The Fgfr2c C342Y mutation results in constitutive activation of the receptor and is associated with upregulation of osteogenic differentiation. Crouzon syndrome mice show premature closure of the coronal suture and other craniofacial anomalies including malocclusion of teeth, most likely due to abnormal craniofacial form. Malformation of the mandible can precipitate a plethora of complications including disrupting development of the upper jaw and palate, impediment of the airway, and alteration of occlusion necessary for proper mastication. The current paradigm of mandibular development assumes that Meckel's cartilage (MC) serves as a support or model for mandibular bone formation and as a template for the later forming mandible. If valid, this implies a functional relationship between MC and the forming mandible, so mandibular dysmorphogenesis might be discerned in MC affecting the relationship between MC and mandibular bone. Here we investigate the relationship of MC to mandible development from the early mineralization of the mandible (E13.5) through the initiation of MC degradation at E17.7 using Crouzon syndrome embryos and their unaffected littermates ( ). Differences between genotypes in both MC and mandibular bone are subtle, however MC of embryos is generally longer relative to unaffected littermates at E15.5 with specific aspects remaining relatively large at E17.5. In contrast, mandibular bone is smaller overall in embryos relative to their unaffected littermates at E15.5 with the posterior aspect remaining relatively small at E17.5. At a cellular level, differences are identified between genotypes early (E13.5) followed by reduced proliferation in MC (E15.5) and in the forming mandible (E17.5) in embryos. Activation of the ERK pathways is reduced in the perichondrium of MC in embryos and increased in bone related cells at E15.5. These data reveal that the Fgfr2c C342Y mutation differentially affects cells by type, location, and developmental age indicating a complex set of changes in the cells that make up the lower jaw.
PubMed: 35651944
DOI: 10.3389/fgene.2022.871927 -
Eye (London, England) May 2022To determine visual outcomes and prevalence of amblyogenic risk factors in children with Apert, Crouzon, Pfeiffer and Saethre-Chotzen syndromes. (Review)
Review
OBJECTIVE
To determine visual outcomes and prevalence of amblyogenic risk factors in children with Apert, Crouzon, Pfeiffer and Saethre-Chotzen syndromes.
METHODS
We conducted a single-centre, retrospective chart review of patients assessed at our unit between October 2000 and May 2017. Our outcome measures were as follows: age at first and last examination, refraction, horizontal ocular alignment, alphabet pattern deviations, anterior segment appearance, fundus examination findings, visual evoked potentials (VEPs) and genetics. The study's primary endpoint was the proportion of children achieving best-corrected visual acuity (BCVA) ≥ 6/12 in the better eye at final visit, as per UK driving standards.
RESULTS
165 patients were included in this study. Breakdown of diagnoses was as follows: Crouzon (n = 60), Apert (n = 57), Pfeiffer (n = 14) and Saethre-Chotzen (n = 34). 98 patients were male. Of 133 patients with full BCVA data available, 76.7% achieved BCVA ≥ 6/12 in the better eye. Of 122 patients, anisometropia >1.00 dioptre sphere (DS) affected 18.9% and astigmatism ≥1.00DS in at least one eye affected 67.2%. Of 246 eyes, 48.4% had oblique astigmatism. Of 165 patients, 60 had exotropia and 12 had esotropia. 48 of 99 patients demonstrated 'V' pattern. On multivariable logistic regression, nystagmus (p = 0.009) and ON involvement (p = 0.001) were associated with decreased vision in the worse eye. Normal VEPs were associated with better BCVA (p = 0.036).
CONCLUSION
There was a high prevalence of amblyogenic factors, however, the majority achieved BCVA ≥ 6/12 in their better eye. Optic neuropathy and nystagmus had the most significant impact on vision. VEPs can help the in overall assessment of visual function.
Topics: Acrocephalosyndactylia; Astigmatism; Child; Craniosynostoses; Evoked Potentials, Visual; Eye Diseases; Female; Humans; Male; Retrospective Studies
PubMed: 33972704
DOI: 10.1038/s41433-021-01458-5 -
Radiology Case Reports May 2020Pfeiffer syndrome is an uncommon autosomal dominant disorder that results in craniosynostosis of multiple calvarial sutures with resulting abnormal facies and...
Pfeiffer syndrome is an uncommon autosomal dominant disorder that results in craniosynostosis of multiple calvarial sutures with resulting abnormal facies and turribrachycephaly. Presented here is a case of Pfeiffer syndrome type II demonstrating a cloverleaf skull configuration and multiple facial and skull base abnormalities characteristic of the disorder. The constellation of findings consistent with Pfeiffer syndrome type II described here provides imaging depictions helpful to the radiologist who may be able to suggest genetic testing for this disorder.
PubMed: 32128008
DOI: 10.1016/j.radcr.2020.01.034 -
Medicina Oral, Patologia Oral Y Cirugia... Jan 2015Pfeiffer syndrome (PS) is mainly characterized by craniosysnostosis, midface hypoplasia, great toes with partial syndactyly of the digits, broad and medially deviated...
Pfeiffer syndrome (PS) is mainly characterized by craniosysnostosis, midface hypoplasia, great toes with partial syndactyly of the digits, broad and medially deviated thumbs. It is caused by allelic mutations in the fibroblast growth factor receptor 1 and 2 (FGFR1 and 2) genes. This study describes the clinical and genetic features of five Brazilian families affected by PS. All patients exhibited the classical phenotypes related to PS. The genetic analysis was able to detect the mutations Cys278Phe, Cys342Arg, and Val359Leu in three of these families. Two mutations were de novo, with one familial. We identified pathogenic mutations in four PS cases in five Brazilian families by PCR sequencing of FGFR1 exon 5 and FGFR2 exons 5, 8, 10, 11, 15, and 16. The clinical and genetic aspects of these families confirm that this syndrome can be clinically variable, with different mutations in the FGFR2 responsible for PS.
Topics: Acrocephalosyndactylia; Adolescent; Adult; Brazil; Child; Child, Preschool; Female; Humans; Male; Middle Aged; Mutation; Pedigree; Phenotype
PubMed: 25129254
DOI: 10.4317/medoral.20032