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"Clinical Report"
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Ex vivo model predicted in vivo efficacy of CFTR modulator therapy in a child with rare genotype
Background New drugs that target the basic defect in cystic fibrosis (CF) patients may now be used in a large number of patients carrying responsive mutations. Nevertheless, further research is needed to extend the benefit of these treatments to patients with rare mutations that are still uncharacterized in vitro and that are not included in clinical trials. For this purpose, ex vivo models are necessary to preliminary assessing the effect of CFTR modulators in these cases. Method We report the clinical effectiveness of lumacaftor/ivacaftor therapy prescribed to a CF child with a rare genetic profile (p.Phe508del/p.Gly970Asp) after testing the drug on nasal epithelial cells. We observed a significant drop of the sweat chloride value, as of the lung clearance index. A longer follow‐up period is needed to define the effects of therapy on pancreatic status, although an increase of the fecal elastase values was found. Conclusion Drug response obtained on nasal epithelial cells correlates with changes in vivo therapeutic endpoints and can be a predictor of clinical efficacy of novel drugs especially in pediatric patients. Drug response obtained on nasal epithelial cells correlates with changes in vivo therapeutic endpoints and can be a predictor of clinical efficacy of novel drugs especially in pediatric patients.
Journal Article
Use of an Endoloop Ligature and a 2-Portal Coelioscopic Approach for the Removal of an Arrowhead Foreign Body in a Red-Tailed Hawk (Buteo jamaicensis)
A juvenile red-tailed hawk (Buteo jamaicensis) was presented to the Ontario Veterinary College from a wildlife rehabilitation facility for the assessment of an arrowhead foreign body injury. The hawk was found on the ground with the left wing in a dropped position. Radiographic images revealed an arrowhead foreign body superimposed over the left lung and thoracic air sacs, immediately medial to the ribs on the ventrodorsal view, and ventral to the scapulae on the right latero-lateral view. A coelioscopy was performed using a left lateral approach with a 2.7-mm rigid endoscope into the left caudal thoracic air sac, with an additional instrument port through the left abdominal air sac. The arrowhead was visualized adjacent to the left lung, separated from the cranial thoracic air sac cavity by a membrane of fibrous tissue. The tissue membrane was radiosurgically incised. Forceps were then used to guide an Endoloop around the arrowhead. The arrowhead was secured by tightening the Endoloop, and the body wall incision was extended to facilitate the arrowhead extraction.
Journal Article
Chorioretinal atrophy following voretigene neparvovec despite the presence of fundus autofluorescence
Introduction Leber congenital amaurosis (LCA) type 2, due to disease‐causing variants in RPE65, is characterized by severe visual loss in early infancy. Current treatments include voretigene neparvovec‐rzyl (VN) for RPE65‐associated LCA. Herein, we present the long‐term follow‐up of a patient treated with VN using quantitative autofluorescence (488 nm excitation). Case Report A 9‐year‐old girl with a diagnosis of LCA with biallelic variants in RPE65 presented for evaluation. The patient underwent VN treatment at the age of 11. The patient returned to clinic at age of 19 at which time imaging revealed evidence of chorioretinal atrophy. Quantitative autofluorescence performed prior to gene therapy and at 6‐ and 8‐year follow‐up revealed a central area of fundus autofluorescence. Discussion This case report demonstrates acquisition of fundus autofluorescence at 6‐ and 8‐year follow‐up despite the development of chorioretinal atrophy. We present eight‐year follow‐up of a patient treated with voretigiene neparvovec‐rzyl (VN) who presented with chorioretinal atrophy at eight‐year follow‐up. Quantitative autofluorescence at six‐ and eight‐year follow‐up demonstrates presence of autofluorescence suggestive of the continued efficacy of VN despite the presence of chorioretinal atrophy.
Journal Article
Retrobulbar Adenocarcinoma with Subconjunctival Extension in a Common Buzzard (Buteo buteo)
A free ranging, fledged common buzzard (Buteo buteo) was found with severe feather damage and left periorbital swelling. Clinical examination revealed a 3.0 × 2.5 × 1.5 cm left medial subconjunctival mass. The abnormal tissue extended over most of the left cornea, severely impairing the bird's vision in that eye. Additionally, the left globe was displaced in a temporal direction. Computed tomography revealed the origin of the mass to be retrobulbar tissue. An ultrasound examination of the mass found cystic areas, and a sanguineous fluid was aspirated. Cytological examination of the aspirated fluid revealed numerous erythrocytes and a few round cells with oval nuclei, single large nucleoli, and abundant foamy cytoplasm. After a poor prognosis for rehabilitation to the wild, the bird was humanely euthanatized. A postmortem examination of the bird confirmed the retrobulbar mass with extension around the bulbus. Histological examination of the mass was consistent with an invasive adenocarcinoma, likely arising from the lacrimal glands. Neoplasia in the orbit has occasionally been described in Psittaciformes, but only rarely in birds of prey such as Accipitriformes.
Journal Article
Atypical mandibulofacial dysostosis with microcephaly diagnosed through the identification of a novel pathogenic mutation in EFTUD2
Background Mandibulofacial dysostosis with microcephaly (MFDM, OMIM# 610536) is a rare monogenic disease that is caused by a mutation in the elongation factor Tu GTP binding domain containing 2 gene (EFTUD2, OMIM* 603892). It is characterized by mandibulofacial dysplasia, microcephaly, malformed ears, cleft palate, growth and intellectual disability. MFDM can be easily misdiagnosed due to its phenotypic overlap with other craniofacial dysostosis syndromes. The clinical presentation of MFDM is highly variable among patients. Methods A patient with craniofacial anomalies was enrolled and evaluated by a multidisciplinary team. To make a definitive diagnosis, whole‐exome sequencing was performed, followed by validation by Sanger sequencing. Results The patient presented with extensive facial bone dysostosis, upward slanting palpebral fissures, outer and middle ear malformation, a previously unreported orbit anomaly, and spina bifida occulta. A novel, pathogenic insertion mutation (c.215_216insT: p.Tyr73Valfs*4) in EFTUD2 was identified as the likely cause of the disease. Conclusions We diagnosed this atypical case of MFDM by the detection of a novel pathogenetic mutation in EFTUD2. We also observed previously unreported features. These findings enrich both the genotypic and phenotypic spectrum of MFDM. This study reported an untypical patient with mandibulofacial dysostosis with microcephaly (MFDM), who exhibited previously unreported phenotypes, including orbit anomalies and spina bifida occulta. A novel pathogenic insertion mutation of EFTUD2 was identified by whole‐exome sequencing as the etiology for this MFDM case, highlighting the importance of genetic diagnosis in patients with craniofacial dysostosis.
Journal Article
Parental mosaicism rather than de novo variants in FOXG1‐related syndrome and TUBA1A‐associated Tubulinopathy: Familial case reports
Background De novo variations are a primary cause of Rett syndrome and Tubulinopathy, accounting for over 90% of cases. Some studies have identified and documented parental inheritance by mosaicism in these two disorders, albeit with limited data. Methods Clinical characteristics and diagnosis, including genetic tests of members of two families, were obtained from medical reports. Results The first family with Rett syndrome (RTT) presented with two offspring carrying FOXG1 c.460dup. Both affected RTT pregnancies did not show anomalies within the first trimester, preventing prenatal recognition at an early stage. The second family had two of three offspring confirmed with TUBA1A c.172G>A related to Tubulinopathy. Both young couples from the two families harbored none of the variants correlating to their children's conditions. Diagnosis of parental mosaics with higher rates of recurrence was reasonably determined, and genetic counseling played a major role in guiding and managing their subsequent pregnancies. Conclusion In genetic disorders with a high penetration of de novo variants, the risk of having a recurrent baby is an important topic to discuss with affected families. By examining variants that siblings share, clinical diagnosis can offer valuable information about the presence of mosaic inheritance. To effectively manage in the long term, adequate genetic counseling and strategic planning for future pregnancies should be emphasized to mitigate the risk of recurrent offspring.
Journal Article
Rare variants in PKHD1 associated with Caroli syndrome: Two case reports
Background Caroli disease (CD, OMIM #600643) is a rare autosomal recessive disorder characterized by polycystic segmental dilatation of the intrahepatic bile ducts and extreme variability in age of onset and clinical manifestations. When congenital hepatic fibrosis is associated with the polycystic dilatation of the biliary tract, the condition is referred as Caroli syndrome. The disease is thought to be caused by pathogenic variants in the PKHD1 gene (OMIM *606702). Method We report the clinical, biochemical, and molecular characterization of three patients with a clinical suspicion of CS belonging to two different families. The genetic screening was performed using a target custom panel and sequencing was performed on Illumina platform. Results Genetic analysis revealed the presence of rare variants in the PKHD1 gene of the analyzed patients. In the first case, and his younger sister, two pathogenic variants (c.2702A>C and c.4870C>T) were found to be associated with a hepatic phenotype at clinical onset, followed by renal disease probably age‐related; while in the second case, one pathogenic variant (c.5879C>G) and a complex allele with uncertain clinical significance [c.3407A>G; c.8345G>C; c.8606C>A] were found to be associated with a severe hepatic phenotype. Conclusion The identification of the genetic causes of the disease and their relationship with the clinical phenotype could have a favorable impact on clinical management and complication prevention. Caroli disease (CD, OMIM #600643) is a rare autosomal recessive disorder characterized by polycystic segmental dilatation of the intrahepatic bile ducts. CD is thought to be caused by pathogenic variants in the PKHD1 gene. We report the clinical, biochemical and molecular characterization of 3 patients with a clinical suspicion of CD belonging to 2 different families. Identifying the genetic causes of the disease is of great significance in order to prevent complications, while improving the patient follow‐up and clinical management.
Journal Article
Noninvasive prenatal screening in a pregnant woman with a history of stem cell transplant from a male donor: A case report and literature review
Background As a screening method, inaccuracies in noninvasive prenatal screening (NIPS) exist, which are often attributable to biological factors. One such factor is the history of transplantation. However, there are still limited reports on such NIPS cases. Methods We report an NIPS case of a pregnant woman who had received a stem cell transplant from a male donor. To determine the karyotype in the woman's original cell, we performed chromosome microarray analysis (CMA) on her postnatal blood and oral mucosa. To comprehensively estimate the cell‐free DNA (cfDNA) composition, we further performed standard NIPS procedures on the postnatal plasma. Moreover, we reviewed all published relevant NIPS case reports about pregnant women with transplantation history. Results NIPS showed a low‐risk result for common trisomies with a fetal fraction of 65.80%. CMA on maternal white blood cells showed a nonmosaic male karyotype, while the oral mucosa showed a nonmosaic female karyotype. The proportion of donor's cfDNA in postnatal plasma was 94.73% based on the Y‐chromosome reads ratio. The composition of cfDNA in maternal plasma was estimated as follows: prenatally, 13.60% maternal, 65.80% donor, and 20.60% fetal/placental, whereas postnatally, 5.27% maternal and 94.73% donor. Conclusions This study expanded our understanding of the influence of stem cell transplantation on NIPS, allowing us to optimize NIPS management for these women. Currently, few noninvasive prenatal screening cases with a transplantation history have been studied. Here, we presented one such case and analyzed its underlying influence by comprehensively investigating the cfDNA composition in the maternal plasma. Our previous reports allow us to optimize the clinical management for these women during prenatal screening.
Journal Article
Case report: Compound heterozygous nonsense PCDH15 variant and a novel deep‐intronic variant in a Chinese child with profound hearing loss
Background Usher syndrome is a condition characterized by partial or total hearing loss and progressive pigmentary retinopathy. Usher syndrome type 1F is caused by biallelic loss‐of‐function variants in Protocadherin 15 (PCDH15), which encodes the PCDH15 protein that plays an important role in the morphogenesis and cohesion of stereocilium bundles and retinal photoreceptor cell maintenance and function. Methods We report a child with bilateral nonsyndromic sensorineural hearing loss who received an inconclusive diagnosis based on clinical gene panel testing, which identified a paternal heterozygous nonsense variant (NM_033056.4: c.733C>T, p.R245*) in PCDH15. This variant has been described as a founder variant in the Ashkenazi Jewish population. Results A novel deep‐intronic variant (NM_033056.4: c.705+3767_705+3768del) inherited from the patient's mother was identified by trio‐based whole‐genome sequencing (WGS). A minigene splicing assay revealed that c.705+3767_705+3768del results in aberrant retention of 50 or 68 bp of intron 7. Conclusion Our genetic test results provided precise genetic counseling and prenatal diagnosis for this family, and our findings highlight the power of WGS for detecting deep‐intronic variants in patients with undiagnosed rare diseases. Additionally, this case expands the variant spectrum of the PCDH15 gene and our results support the extremely low carrier frequency of c.733C>T in the Chinese population. We reported a child with profound bilateral non‐syndromic sensorineural hearing and compound heterozygosity for a common nonsense and novel deep intronic variant that was identified by WGS. The results of genetic testing provided precise genetic counseling and prenatal diagnosis for this family and was contributed to diagnose other USH1F patients in the future. Our findings highlight the power of WGS for detecting deep‐intronic variants in patients with undiagnosed rare diseases. Additionally, this case expands the variant spectrum of the PCDH15 gene, and our results support the extremely low carrier frequency of c.733C>T in the Chinese population.
Journal Article