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| 2. |
- Casslén, Beatrice, et al.
(författare)
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Visual function and quality of life in children and adolescents with anophthalmia and microphthalmia treated with ocular prosthesis
- 2020
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Ingår i: Acta Ophthalmologica. - : Wiley. - 1755-375X .- 1755-3768. ; 98:7, s. 662-670
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To evaluate health-related quality of life (HR-QoL), vision-related (VR-)QoL and perceptual visual dysfunction (PVD) among individuals with anophthalmia (A) and microphthalmia (M) treated with ocular prosthesis. Methods The study comprised 15 individuals (mean age 6.6 years; range 1.7-14.1) with unilateral A or M. Three validated instruments measuring HR-QoL and VR-QoL were used: The Pediatric QoL Inventory (PedsQL), consisting of physical and psychosocial self-report and parent-proxy report (2-18 years); Children's Visual Function Questionnaire (CVFQ); and Effects of Youngsters' Eyesight on Quality of Life (EYE-Q). Perceptual visual dysfunctions (PVDs) were assessed by history taking according to a specific protocol. Results A/M children and their parents showed low HR-QoL scores (PedsQL total score: 66.3; 69.6) compared with controls (83.0; 87.61) (p = 0.0035 and <0.0001, respectively, unpaired t-test). No differences were found between A/M children and parents, but parents tended to underestimate their children's emotional state. A/M children with subnormal visual acuity (VA) for age scored lower in physical health compared with A/M children with normal VA (p = 0.03, Mann-Whitney U-test). No significant VR-QoL differences between A/M children and references or between A/M children with subnormal or normal VA for age were found. More A/M children than controls exhibited PVDs in >= 1 area (7/11 versus 4/118; p < 0.0001, Fisher's exact test). Conclusion A/M individuals show poor HR-QoL and increased PVDs. No difference in QoL was found between children and parents, though the children tended to score lower in emotional well-being. A/M children with subnormal VA showed lower physical health score. These problems indicate the necessity of a thorough multidisciplinary assessment and follow-up of children with A/M.
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- Taha Najim, Rezhna, et al.
(författare)
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Children and young adults with anophthalmia and microphthalmia : Diagnosis and Management
- 2020
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Ingår i: Acta Ophthalmologica. - : John Wiley & Sons. - 1755-375X .- 1755-3768. ; 98:8, s. 848-858
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Congenital anophthalmia (A) and microphthalmia (M) are rare developmental defects, which could be isolated or syndromic. Our objective was to describe a cohort of children and young adults with A/M treated with ocular prosthesis, emphasizing clinical features, diagnosis, treatment, and follow-up.METHODS: Eighteen individuals (10 female) with unilateral A (n = 3) and M (n = 15) with a mean age of 9.5 years (range 0.8-31.8) and treated with ocular prosthesis were included. Data on medical history, clinical examinations and management of ocular prosthesis were collected. Genetic screening with microarray and whole-exome sequencing targeting 121 A/M-related genes was performed.RESULTS: A/M appeared isolated (seven cases) or as part of a syndromic condition (11 cases). In 4/16 patients, mutations were detected in TFAP2A, CHD7, FOXE3 and BCOR-genes. In one patient, a possibly causal microdeletion 10q11 was shown. Associated ocular anomalies such as cataract and cysts were found in 16 (89%) of the A/M eyes, and in nine (50%) ophthalmological findings were found in the fellow eyes. The median ages at which the conformer and ocular prosthesis first were initiated were 7.8 months and 1.5 years. 16/17 patients fulfilled satisfactory orbital growth and cosmetic results when treated with ocular prosthesis from an early age.CONCLUSION: Based upon our findings, a multidisciplinary approach, including genetic assessment, is necessary to cover all aspects of A/M. Imaging, ultrasound and visual evoked potentials should be included. Early management is crucial for the outcome, in terms of non-ocular findings, vision in the fellow eye, and for facial cosmetic development.
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- Topa, Alexandra, 1978
(författare)
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Genetic studies of craniosynostosis with focus on syndromic forms
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Craniosynostosis (CS) represents the premature closure of skull sutures and affects ~1 in 2500 children. Untreated CS can lead to significant complications in craniofacial and psychomotor development. The only treatment available is surgical and requires access to highly specialized healthcare. The development of alternative and/or complementary therapeutic methods relies on an understanding of the intricate molecular and cellular mechanisms underlying CS. Genetic studies are of clinical importance to establish an etiologic diagnosis of inheritable craniofacial syndromes and enable patient prognosis and follow-up, including assessment of the recurrence risk in the family (genetic counseling). The aim of this thesis was to study the prevalence and spectrum of genetic alterations associated with CS in a retrospective cohort of patients that underwent surgery at the largest reference center in Sweden. The patients were initially screened with a targeted next-generation sequencing (NGS) panel covering CS-related genes. Patients with negative outcome were subsequently analyzed using whole-genome or whole-exome sequencing (WGS and WES, respectively). The results showed that targeted NGS screening demonstrated a high diagnostic yield in patients with syndromic forms of CS (>80%) regardless of sutural pattern. The particular case of a patient with coronal synostosis and a Kabuki-like phenotype, as well as a simultaneous de novo occurrence of a lysine-specific methyltransferase 2D (KMT2D) mutation and 10q22.3q23.1 microdeletion, suggests that CS may be an underdiagnosed feature of these conditions. Additionally, interleukin-11 receptor subunit α (IL11RA) was highlighted as an emerging core gene for autosomal recessive pansynostosis. The use of WGS/WES detected causal variants in 38% of the patients with rare syndromic forms of CS and a negative outcome at targeted screening. Furthermore, potentially relevant variants were observed in 87% of the remaining patients with syndromic or nonsyndromic forms of CS. These findings showed that both targeted NGS screening and WGS/WES demonstrated a high diagnostic yield in patients with syndromic CS. Moreover, the results suggested that WES/WGS has the potential to become a unique diagnostic tool that can be adapted to the phenotypic presentation by initial use of in silico gene panels, followed by exome/genome-wide analysis of rare forms of CS.
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| 6. |
- Topa, Alexandra, 1978, et al.
(författare)
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NGS targeted screening of 100 Scandinavian patients with coronal synostosis
- 2020
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Ingår i: American Journal of Medical Genetics Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 182:2, s. 348-356
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Tidskriftsartikel (refereegranskat)abstract
- Craniosynostosis (CS), the premature closure of one or more cranial sutures, occurs both as part of a syndrome or in isolation (nonsyndromic form). Here, we have studied the prevalence and spectrum of genetic alterations associated with coronal suture closure in 100 Scandinavian patients treated at a single craniofacial unit. All patients were phenotypically assessed and analyzed with a custom-designed 63 gene NGS-panel. Most cases (78%) were syndromic forms of CS. Pathogenic and likely pathogenic variants explaining the phenotype were found in 80% of the families with syndromic CS and in 14% of those with nonsyndromic CS. Sixty-five percent of the families had mutations in the CS core genes FGFR2, TWIST1, FGFR3, TCF12, EFNB1, FGFR1, and POR. Five novel pathogenic/likely pathogenic variants in TWIST1, TCF12, and EFNB1 were identified. We also found novel variants in SPECC1L, IGF1R, and CYP26B1 with a possible modulator phenotypic effect. Our findings demonstrate that NGS targeted sequencing is a powerful tool to detect pathogenic mutations in patients with coronal CS and further emphasize the importance of thorough assessment of the patient's phenotype for reliable interpretation of the molecular findings. This is particularly important in patients with complex phenotypes and rare forms of CS.
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| 7. |
- Topa, Alexandra, 1978, et al.
(författare)
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On the significance of craniosynostosis in a case of Kabuki syndrome with a concomitant KMT2D mutation and 3.2 Mbp de novo 10q22.3q23.1 deletion
- 2017
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Ingår i: American Journal of Medical Genetics Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 173:8, s. 2219-2225
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Tidskriftsartikel (refereegranskat)abstract
- Craniosynostosis has rarely been described in patients with Kabuki syndrome. We report here a boy with facial asymmetry due to combined premature synostosis of the right coronal and sagittal sutures as well as several symptoms reminiscent of Kabuki syndrome (KS). Our case supports previous observations and suggests that craniosynostosis is a part of the KS phenotype. The uniqueness of our case is the sporadic co-occurrence of two genetic disorders, that is, a de novo frameshift variant in the KMT2D gene and a de novo 3.2 Mbp 10q22.3q23.1 deletion. Our findings emphasize the importance of the initial clinical assessment of children with craniosynostosis and that genomic and monogenic disorders, such as Kabuki syndrome, should be considered among the differential diagnoses of syndromic forms of craniosynostosis.
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| 8. |
- Topa, Alexandra, 1978, et al.
(författare)
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The outcome of targeted NGS screening in patients with syndromic forms of sagittal and pansynostosis-IL11RA is an emerging core-gene for pansynostosis
- 2022
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Ingår i: European Journal of Medical Genetics. - : Elsevier BV. - 1769-7212. ; 65:5
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Tidskriftsartikel (refereegranskat)abstract
- Here, we have studied the prevalence and spectrum of genetic alterations in syndromic forms of sagittal and pansynostosis. Eighteen patients with sagittal synostosis (isolated or combined with other synostoses, except coronal) or pansynostosis were phenotypically assessed by retrospective analysis of medical records, threedimensional computed tomography skull reconstructions, and registered photos. Patient DNAs were analyzed using a targeted next-generation sequencing (NGS) panel including 63 craniosynostosis (CS) related genes. Pathogenic and likely pathogenic variants were found in 72% of the cases, mainly affecting FGFR2, TWIST1, IL11RA, and SKI. Two patients that were negative at NGS screening - one with a supernumerary marker chromosome with duplication of 15q25.2q26.3 and one with a pathogenic PHEX variant - were identified using microarray and single gene analysis, respectively. The overall diagnostic rate in the cohort was thus 83%. We identified two novel likely pathogenic variants in FGFR2 (NM_022970.3: c.811_812delGGinsCC, p.Gly271Pro) and TWIST1 (NM_000474.3: c.476T > A, p.Leu159His), and a novel variant of unclear phenotypic significance in RUNX2 (NM_001024630.3: c.340G > A, p.Val114Ile) which could suggest a modulatory effect. Notably, we also identified three new patients with pansynostosis and a Crouzon-like phenotype with IL11RA mutation. Targeted NGS using a broad panel of CS-related genes is a simple and powerful tool for detecting pathogenic mutations in patients with syndromic forms of CS and multiple suture involvement, in particular pansynostosis. Our results provide additional evidence of an association between pansynostosis and IL11RA, an emerging core gene for autosomal recessive CS.
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| 9. |
- Topa, Alexandra, 1978, et al.
(författare)
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The value of genome-wide analysis in craniosynostosis
- 2024
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Ingår i: FRONTIERS IN GENETICS. - 1664-8021. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: This study assessed the diagnostic yield of high-throughput sequencing methods in a cohort of craniosynostosis (CS) patients not presenting causal variants identified through previous targeted analysis.Methods: Whole-genome or whole-exome sequencing (WGS/WES) was performed in a cohort of 59 patients (from 57 families) assessed by retrospective phenotyping as having syndromic or nonsyndromic CS.Results: A syndromic form was identified in 51% of the unrelated cases. A genetic cause was identified in 38% of syndromic cases, with novel variants detected in FGFR2 (a rare Alu insertion), TWIST1, TCF12, KIAA0586, HDAC9, FOXP1, and NSD2. Additionally, we report two patients with rare recurrent variants in KAT6A and YY1 as well as two patients with structural genomic aberrations: one with a 22q13 duplication and one with a complex rearrangement involving chromosome 2 (2p25 duplication including SOX11 and deletion of 2q22). Moreover, we identified potentially relevant variants in 87% of the remaining families with no previously detected causal variants, including novel variants in ADAMTSL4, ASH1L, ATRX, C2CD3, CHD5, ERF, H4C5, IFT122, IFT140, KDM6B, KMT2D, LTBP1, MAP3K7, NOTCH2, NSD1, SOS1, SPRY1, POLR2A, PRRX1, RECQL4, TAB2, TAOK1, TET3, TGFBR1, TCF20, and ZBTB20.Conclusion: These results confirm WGS/WES as a powerful diagnostic tool capable of either targeted in silico or broad genomic analysis depending on phenotypic presentation (e.g., classical or unusual forms of syndromic CS).
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