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M P Snead - One of the best experts on this subject based on the ideXlab platform.
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Stickler Syndrome airway complications in a case series of 502 patients
Anesthesia & Analgesia, 2021Co-Authors: Julia Zimmermann, Annie Mcninch, A J Richards, Philip Alexander, Daniel J Stubbs, Basil F Matta, M P SneadAbstract:Background Patients with Stickler Syndrome often require emergency surgery and are often anesthetized in nonspecialist units, typically for retinal detachment repair. Despite the occurrence of cleft palate and Pierre-Robin sequence, there is little published literature on airway complications. Our aim was to describe anesthetic practice and complications in a nonselected series of Stickler Syndrome cases. To our knowledge, this is the largest such series in the published literature. Methods We retrospectively identified patients with genetically confirmed Stickler Syndrome who had undergone general anesthesia in a major teaching hospital, seeking to identify factors that predicted patients who would require more than 1 attempt to correctly site an endotracheal tube (ETT) or supraglottic airway device (SAD). Patient demographics, associated factors, and anesthetic complications were collected. Descriptive statistical analysis and logistic regression modeling were performed. Results Five hundred and two anesthetic events were analyzed. Three hundred ninety-five (92.7%) type 1 Stickler and 63 (96.9%) type 2 Stickler patients could be managed with a single attempt of passing an ETT or SAD. Advanced airway techniques were required on 4 occasions, and we report no major complications. On logistic regression, modeling receding mandible (P = .0004) and history of cleft palate (P = .0004) were significantly associated with the need for more than 1 attempt at airway manipulation. Conclusions The majority of Stickler patients can be anesthetized safely with standard management. If patients have a receding mandible or history of cleft, an experienced anesthetist familiar with Stickler Syndrome should manage the patient. We recommend that patients identified to have a difficult airway wear an alert bracelet.
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Stickler Syndrome in children a radiological review
Clinical Radiology, 2018Co-Authors: N Mcarthur, Annie Mcninch, A J Richards, Arabella V. Poulson, A Rehm, Nick Shenker, J Tanner, M P Snead, P W P BearcroftAbstract:Aim To review the radiological findings of the largest cohort to date of paediatric patients with Stickler Syndrome, all with confirmed molecular genetic analysis and sub-typing. Patients and methods It is understood that the National Health Service (NHS) commissioned service at Addenbrookes Hospital, Cambridge, UK has the largest cohort of Stickler Syndrome patients in the paediatric age group worldwide with 240 registered children. Fifty-nine were assessed radiologically and for their genotypes. These radiographs were reviewed and 74 knee, 45 pelvic, and 47 spinal examinations were evaluated. Results Radiological features were noted in 45.9% of knee radiographs, 11.1% of pelvic radiographs, and 42.6% of spinal radiographs. The findings were reviewed in the light of each patient's specific genetic Stickler Syndrome subtype. Conclusion The prevalence of orthopaedic abnormalities overall in the present series is substantially below those published in previous smaller case series. This would support the more recent findings of an array of ocular only phenotypes of Stickler Syndrome described in the literature.
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prevention of retinal detachment in Stickler Syndrome the cambridge prophylactic cryotherapy protocol
Ophthalmology, 2014Co-Authors: Gregory S. Fincham, Annie Mcninch, A J Richards, Arabella V. Poulson, J D Scott, Laura Pasea, Christopher Carroll, M P SneadAbstract:Purpose: The Stickler Syndromes are the most common causes of inherited and childhood retinal detachment; however, no consensus exists regarding the effectiveness of prophylactic intervention. We evaluate the long-term safety and efficacy of the Cambridge prophylactic cryotherapy protocol, a standardized retinal prophylactic treatment developed to prevent retinal detachment arising from giant retinal tears in type 1 Stickler Syndrome. Design: Retrospective comparative case series. Participants: Four hundred eighty seven patients with type 1 Stickler Syndrome. Methods: Time to retinal detachment was compared between patients who received bilateral prophylaxis and untreated controls, with and without individual patient matching. Patients receiving unilateral prophylaxis (after fellow eye retinal detachment) were similarly compared with an appropriate control subgroup. Individual patient matching ensured equal age and follow-up between groups and that an appropriate control (who had not suffered a retinal detachment before the age at which their individually matched treatment patient underwent prophylactic treatment) was selected. Matching was blinded to outcome events. Individual patient matching protocols purposely weighted bias against the effectiveness of treatment. All treatment side effects are reported. Main Outcome Measures: Time to retinal detachment and side effects occurring after prophylactic treatment. Results: The bilateral control group (n ¼ 194) had a 7.4-fold increased risk of retinal detachment compared to the bilateral prophylaxis group (n ¼ 229) (hazard ratio [HR], 7.40; 95% confi dence interval [CI], 4.53e12.08; P<0.001); the matched bilateral control group (n ¼ 165) had a 5.0-fold increased risk compared to the matched bilateral prophylaxis group (n ¼ 165) (HR, 4.97; 95% CI, 2.82e8.78; P<0.001). The unilateral control group (n ¼ 104) had a 10.3-fold increased risk of retinal detachment compared to the unilateral prophylaxis group (n ¼ 64) (HR, 10.29; 95% CI, 4.96e21.36; P<0.001); the matched unilateral control group (n ¼ 39) had a 8.4-fold increased risk compared to the matched unilateral prophylaxis group (n ¼ 39) (HR, 8.36; 95% CI, 3.24e21.57; P<0.001). No significant long-term side effects occurred. Conclusions: In the largest global cohort of type 1 Stickler Syndrome patients published, all analyses indicate that the Cambridge prophylactic cryotherapy protocol is safe and markedly reduces the risk of retinal detachment. Ophthalmology 2014;121:1588-1597 a 2014 by the American Academy of Ophthalmology.
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alternative splicing modifies the effect of mutations in col11a1 and results in recessive type 2 Stickler Syndrome with profound hearing loss
Journal of Medical Genetics, 2013Co-Authors: A J Richards, John D. Scott, Annie Mcninch, Arabella V. Poulson, Gregory S. Fincham, David A Hill, Bruce Castle, Melissa Lees, Anthony T Moore, M P SneadAbstract:Background Stickler Syndromes types 1, 2 and 3 are usually dominant disorders caused by mutations in the genes COL2A1 , COL11A1 and COL11A2 that encode the fibrillar collagens types II and XI present in cartilage and vitreous. Rare recessive forms of Stickler Syndrome exist that are due to mutations in genes encoding type IX collagen ( COL9A1 type 4 Stickler Syndrome and COL9A2 type 5 Stickler Syndrome). Recently, recessive mutations in the COL11A1 gene have been demonstrated to result in fibrochondrogenesis, a much more severe skeletal dysplasia, which is often lethal. Here we demonstrate that some mutations in COL11A1 are recessive, modified by alternative splicing and result in type 2 Stickler Syndrome rather than fibrochondrogenesis. Methods Patients referred to the national Stickler Syndrome diagnostic service for England, UK were assessed clinically and subsequently sequenced for mutations in COL11A1 . Additional in silico and functional studies to assess the effect of sequence variants on pre-mRNA processing and collagen structure were performed. Results In three different families, heterozygous COL11A1 biallelic null, null/missense or silent/missense mutations, were found. They resulted in a recessive form of type 2 Stickler Syndrome characterised by particularly profound hearing loss and are clinically distinct from the recessive types 4 and 5 variants of Stickler Syndrome. One mutant allele in each family is capable of synthesising a normal α1(XI) procollagen molecule, via variable pre-mRNA processing. Conclusion This new variant has important implications for molecular diagnosis and counselling families with type 2 Stickler Syndrome.
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the efficacy and safety of prophylactic cryotherapy in preventing retinal detachment in type 1 Stickler Syndrome
Investigative Ophthalmology & Visual Science, 2013Co-Authors: Gregory S. Fincham, Annie Mcninch, A J Richards, Arabella V. Poulson, Laura Pasea, Christopher Carroll, J P Scott, M P SneadAbstract:BODY: The efficacy and safety of prophylactic cryotherapy in preventing retinal detachment in type 1 Stickler Syndrome Purpose: To evaluate the efficacy and safety of 360° prophylactic cryotherapy (360PC) according to a standardized protocol and rationale in preventing retinal detachment (RD) in type 1 Stickler Syndrome patients. Methods: A retrospective cohort study. Four hundred and eighty seven type 1 Stickler Syndrome patients with both eyes available for study were allocated to a prophylaxis group according to a standardized protocol and rationale (bilateral 360PC) and compared to a control group (no 360PC), or a mixed group (unilateral RD with subsequent unilateral 360PC) and compared to a mixed-control group (unilateral or bilateral RDs with no 360PC) by adjusted multivariant Cox regression and age-matching analyses. All eyes from all patients were also analysed individually to compare the risk of RD with and without prophylaxis, in addition to randomly selecting one eye from each patient for repeated comparison. The main outcome measures were time to RD (including failure of 360PC requiring retinopexy with or without surgery) and side effects resulting from prophylactic treatment. Results: The control group (n=194) had a greater than seven-fold increased risk of RD compared to the prophylaxis group (n=229) (hazard ratio [HR] = 7.4; 95% confidence interval [CI]: 4.5 – 12.1), with the age-matched control group (n=165) having a five-fold increased risk compared to the age-matched prophylaxis group (n=165) (HR = 5.0; 95% CI: 2.8 – 8.8). Similarly, the mixed-control group (n=104) had a greater than ten-fold increased risk of RD compared to the mixed group (n=64) (HR = 10.3; 95% CI: 5.0 – 21.4), with the age-matched mixed-control group (n=39) having a greater than eight-fold increased risk compared to the age-matched mixed group (n=39) (HR = 8.4; 95% CI: 3.3 – 21.6). Analysis of all individually analysed eyes that received no prophylaxis (n=452) indicated a greater than eleven-fold increased risk of RD compared to those that received 360PC (n=522) (HR = 11.7; 95% CI: 7.9 – 17.2), with a greater than fifteen-fold increased risk calculated when one eye from each patient was randomly selected (HR = 15.4; 95% CI 8.1 – 29.3). Reported side effects from prophylactic treatment were minor and shortlived. Conclusions: All analyses indicate that prophylactic retinopexy delivered according to this standardized protocol is safe and markedly reduces the risk of retinal detachment in type 1 Stickler Syndrome.
A J Richards - One of the best experts on this subject based on the ideXlab platform.
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auditory dysfunction in type 2 Stickler Syndrome
European Archives of Oto-rhino-laryngology, 2021Co-Authors: Philip Alexander, Annie Mcninch, A J Richards, Arabella V. Poulson, Gregory S. Fincham, Philip Gomersall, Jack Stancellewis, David M. BaguleyAbstract:To present the extent and site of lesion of auditory dysfunction in a large cohort of individuals with type 2 Stickler Syndrome. Type 2 Stickler Syndrome results from a mutation in the gene coding for α-1 type XI pro-collagen, which has been identified in the human vitreous, cartilage and the cochlea of the mouse. The condition is characterised by classic ocular abnormalities, auditory dysfunction, osteoarthropathy and oro-facial dysplasia. This is a population study which used a combination of audiometric, tympanometric, and self-report measures on a series of 65 individuals (mean age 29.2 years, range 3–70, female 63.1%) with genetically confirmed type 2 Stickler Syndrome. Hearing impairment was identified in at least one ear for 69% of individuals. Analysis against age-matched normative data showed that reduced hearing sensitivity was present across all test frequencies. Sensorineural hearing loss was most common (77% of ears), with conductive (3%), mixed (7%) and no hearing loss (13%), respectively. The proportion of hypermobile tympanic membranes (24%) was less than previously documented in type 1 Stickler Syndrome. When present, this appears to arise as a direct result of collagen abnormalities in the middle ear. Self-report measures of speech and spatial hearing in sound were comparable to a non-syndromic cohort with similar audiometric thresholds. Auditory impairment in type 2 Stickler Syndrome is predominantly associated with cochlear hearing loss of varying severities across affected individuals. The impact on hearing thresholds can be seen across the frequency range, suggesting a contribution of defective collagen throughout the cochlea. Self-report questionnaires showed that difficulties understanding speech, and spatial information in sound (such as that used for localisation), were worse than a young, normal-hearing population but comparable to a non-syndromic cohort with similar audiometric thresholds. Therefore, it is likely that hearing loss in type 2 Stickler Syndrome arises in the auditory periphery, without significant central processing deficits.
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Stickler Syndrome airway complications in a case series of 502 patients
Anesthesia & Analgesia, 2021Co-Authors: Julia Zimmermann, Annie Mcninch, A J Richards, Philip Alexander, Daniel J Stubbs, Basil F Matta, M P SneadAbstract:Background Patients with Stickler Syndrome often require emergency surgery and are often anesthetized in nonspecialist units, typically for retinal detachment repair. Despite the occurrence of cleft palate and Pierre-Robin sequence, there is little published literature on airway complications. Our aim was to describe anesthetic practice and complications in a nonselected series of Stickler Syndrome cases. To our knowledge, this is the largest such series in the published literature. Methods We retrospectively identified patients with genetically confirmed Stickler Syndrome who had undergone general anesthesia in a major teaching hospital, seeking to identify factors that predicted patients who would require more than 1 attempt to correctly site an endotracheal tube (ETT) or supraglottic airway device (SAD). Patient demographics, associated factors, and anesthetic complications were collected. Descriptive statistical analysis and logistic regression modeling were performed. Results Five hundred and two anesthetic events were analyzed. Three hundred ninety-five (92.7%) type 1 Stickler and 63 (96.9%) type 2 Stickler patients could be managed with a single attempt of passing an ETT or SAD. Advanced airway techniques were required on 4 occasions, and we report no major complications. On logistic regression, modeling receding mandible (P = .0004) and history of cleft palate (P = .0004) were significantly associated with the need for more than 1 attempt at airway manipulation. Conclusions The majority of Stickler patients can be anesthetized safely with standard management. If patients have a receding mandible or history of cleft, an experienced anesthetist familiar with Stickler Syndrome should manage the patient. We recommend that patients identified to have a difficult airway wear an alert bracelet.
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inherited and de novo biallelic pathogenic variants in col11a1 result in type 2 Stickler Syndrome with severe hearing loss
Molecular Genetics & Genomic Medicine, 2020Co-Authors: Annie Mcninch, A J Richards, Thomas R. W. Nixon, Stephen Abbs, Philip Alexander, Adrian Lomas, Pradeep VasudevanAbstract:Background Type 2 Stickler Syndrome is usually a dominant disorder resulting from pathogenic variants in COL11A1 encoding the alpha 1 chain of type XI collagen. Typical molecular changes result in either substitution of an obligate glycine within the Gly-Xaa-Yaa amino acid sequence repeat region of the molecule, mRNA missplicing or deletions/duplications that typically leaves the message in-frame. Clinical features include myopia, retinal detachment, craniofacial, joint, and hearing problems. Fibrochondrogenesis is also a COL11A1 related disorder, but here disease-associated variants are recessive and may be either null alleles or substitutions of glycine, and the condition is usually lethal in infancy. Methods The patient was assessed in the NHS England Stickler Syndrome diagnostic service. DNA from the patient and family were analyzed with Next Generation Sequencing on a panel of genes known to cause Stickler Syndrome. The effect of sequence variants was assessed using minigene analysis. Allele-specific RT-PCR was performed. Results This patient had clinical type 2 Stickler Syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. We identified a de novo in frame deletion of COL11A1 (c.4109_4126del) consistent with dominantly inherited Stickler Syndrome but also a second inherited variant (c.1245+2T>C), on the other allele, affecting normal splicing of COL11A1 exon 9. Conclusion Exon 9 of COL11A1 is alternatively expressed and disease causing changes affecting only this exon modify the phenotype resulting from biallelic COL11A1 disease-associated variants and, instead of fibrochondrogenesis, produce a form of Stickler Syndrome with severe hearing loss. Disease phenotypes from de novo pathogenic variants can be modified by inherited recessive variants on the other allele. This highlights the need for functional and family analysis to confirm the mode of inheritance in COL11A1-related disorders, particularly for those variants that may alter normal pre-mRNA splicing.
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Stickler Syndrome in children a radiological review
Clinical Radiology, 2018Co-Authors: N Mcarthur, Annie Mcninch, A J Richards, Arabella V. Poulson, A Rehm, Nick Shenker, J Tanner, M P Snead, P W P BearcroftAbstract:Aim To review the radiological findings of the largest cohort to date of paediatric patients with Stickler Syndrome, all with confirmed molecular genetic analysis and sub-typing. Patients and methods It is understood that the National Health Service (NHS) commissioned service at Addenbrookes Hospital, Cambridge, UK has the largest cohort of Stickler Syndrome patients in the paediatric age group worldwide with 240 registered children. Fifty-nine were assessed radiologically and for their genotypes. These radiographs were reviewed and 74 knee, 45 pelvic, and 47 spinal examinations were evaluated. Results Radiological features were noted in 45.9% of knee radiographs, 11.1% of pelvic radiographs, and 42.6% of spinal radiographs. The findings were reviewed in the light of each patient's specific genetic Stickler Syndrome subtype. Conclusion The prevalence of orthopaedic abnormalities overall in the present series is substantially below those published in previous smaller case series. This would support the more recent findings of an array of ocular only phenotypes of Stickler Syndrome described in the literature.
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prevention of retinal detachment in Stickler Syndrome the cambridge prophylactic cryotherapy protocol
Ophthalmology, 2014Co-Authors: Gregory S. Fincham, Annie Mcninch, A J Richards, Arabella V. Poulson, J D Scott, Laura Pasea, Christopher Carroll, M P SneadAbstract:Purpose: The Stickler Syndromes are the most common causes of inherited and childhood retinal detachment; however, no consensus exists regarding the effectiveness of prophylactic intervention. We evaluate the long-term safety and efficacy of the Cambridge prophylactic cryotherapy protocol, a standardized retinal prophylactic treatment developed to prevent retinal detachment arising from giant retinal tears in type 1 Stickler Syndrome. Design: Retrospective comparative case series. Participants: Four hundred eighty seven patients with type 1 Stickler Syndrome. Methods: Time to retinal detachment was compared between patients who received bilateral prophylaxis and untreated controls, with and without individual patient matching. Patients receiving unilateral prophylaxis (after fellow eye retinal detachment) were similarly compared with an appropriate control subgroup. Individual patient matching ensured equal age and follow-up between groups and that an appropriate control (who had not suffered a retinal detachment before the age at which their individually matched treatment patient underwent prophylactic treatment) was selected. Matching was blinded to outcome events. Individual patient matching protocols purposely weighted bias against the effectiveness of treatment. All treatment side effects are reported. Main Outcome Measures: Time to retinal detachment and side effects occurring after prophylactic treatment. Results: The bilateral control group (n ¼ 194) had a 7.4-fold increased risk of retinal detachment compared to the bilateral prophylaxis group (n ¼ 229) (hazard ratio [HR], 7.40; 95% confi dence interval [CI], 4.53e12.08; P<0.001); the matched bilateral control group (n ¼ 165) had a 5.0-fold increased risk compared to the matched bilateral prophylaxis group (n ¼ 165) (HR, 4.97; 95% CI, 2.82e8.78; P<0.001). The unilateral control group (n ¼ 104) had a 10.3-fold increased risk of retinal detachment compared to the unilateral prophylaxis group (n ¼ 64) (HR, 10.29; 95% CI, 4.96e21.36; P<0.001); the matched unilateral control group (n ¼ 39) had a 8.4-fold increased risk compared to the matched unilateral prophylaxis group (n ¼ 39) (HR, 8.36; 95% CI, 3.24e21.57; P<0.001). No significant long-term side effects occurred. Conclusions: In the largest global cohort of type 1 Stickler Syndrome patients published, all analyses indicate that the Cambridge prophylactic cryotherapy protocol is safe and markedly reduces the risk of retinal detachment. Ophthalmology 2014;121:1588-1597 a 2014 by the American Academy of Ophthalmology.
Annie Mcninch - One of the best experts on this subject based on the ideXlab platform.
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auditory dysfunction in type 2 Stickler Syndrome
European Archives of Oto-rhino-laryngology, 2021Co-Authors: Philip Alexander, Annie Mcninch, A J Richards, Arabella V. Poulson, Gregory S. Fincham, Philip Gomersall, Jack Stancellewis, David M. BaguleyAbstract:To present the extent and site of lesion of auditory dysfunction in a large cohort of individuals with type 2 Stickler Syndrome. Type 2 Stickler Syndrome results from a mutation in the gene coding for α-1 type XI pro-collagen, which has been identified in the human vitreous, cartilage and the cochlea of the mouse. The condition is characterised by classic ocular abnormalities, auditory dysfunction, osteoarthropathy and oro-facial dysplasia. This is a population study which used a combination of audiometric, tympanometric, and self-report measures on a series of 65 individuals (mean age 29.2 years, range 3–70, female 63.1%) with genetically confirmed type 2 Stickler Syndrome. Hearing impairment was identified in at least one ear for 69% of individuals. Analysis against age-matched normative data showed that reduced hearing sensitivity was present across all test frequencies. Sensorineural hearing loss was most common (77% of ears), with conductive (3%), mixed (7%) and no hearing loss (13%), respectively. The proportion of hypermobile tympanic membranes (24%) was less than previously documented in type 1 Stickler Syndrome. When present, this appears to arise as a direct result of collagen abnormalities in the middle ear. Self-report measures of speech and spatial hearing in sound were comparable to a non-syndromic cohort with similar audiometric thresholds. Auditory impairment in type 2 Stickler Syndrome is predominantly associated with cochlear hearing loss of varying severities across affected individuals. The impact on hearing thresholds can be seen across the frequency range, suggesting a contribution of defective collagen throughout the cochlea. Self-report questionnaires showed that difficulties understanding speech, and spatial information in sound (such as that used for localisation), were worse than a young, normal-hearing population but comparable to a non-syndromic cohort with similar audiometric thresholds. Therefore, it is likely that hearing loss in type 2 Stickler Syndrome arises in the auditory periphery, without significant central processing deficits.
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Stickler Syndrome airway complications in a case series of 502 patients
Anesthesia & Analgesia, 2021Co-Authors: Julia Zimmermann, Annie Mcninch, A J Richards, Philip Alexander, Daniel J Stubbs, Basil F Matta, M P SneadAbstract:Background Patients with Stickler Syndrome often require emergency surgery and are often anesthetized in nonspecialist units, typically for retinal detachment repair. Despite the occurrence of cleft palate and Pierre-Robin sequence, there is little published literature on airway complications. Our aim was to describe anesthetic practice and complications in a nonselected series of Stickler Syndrome cases. To our knowledge, this is the largest such series in the published literature. Methods We retrospectively identified patients with genetically confirmed Stickler Syndrome who had undergone general anesthesia in a major teaching hospital, seeking to identify factors that predicted patients who would require more than 1 attempt to correctly site an endotracheal tube (ETT) or supraglottic airway device (SAD). Patient demographics, associated factors, and anesthetic complications were collected. Descriptive statistical analysis and logistic regression modeling were performed. Results Five hundred and two anesthetic events were analyzed. Three hundred ninety-five (92.7%) type 1 Stickler and 63 (96.9%) type 2 Stickler patients could be managed with a single attempt of passing an ETT or SAD. Advanced airway techniques were required on 4 occasions, and we report no major complications. On logistic regression, modeling receding mandible (P = .0004) and history of cleft palate (P = .0004) were significantly associated with the need for more than 1 attempt at airway manipulation. Conclusions The majority of Stickler patients can be anesthetized safely with standard management. If patients have a receding mandible or history of cleft, an experienced anesthetist familiar with Stickler Syndrome should manage the patient. We recommend that patients identified to have a difficult airway wear an alert bracelet.
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Auditory dysfunction in type 2 Stickler Syndrome
European Archives of Oto-Rhino-Laryngology, 2020Co-Authors: Philip Alexander, Allan Richards, Annie Mcninch, Arabella Poulson, Philip Gomersall, Jack Stancel-lewis, Gregory Scott Fincham, David M. Baguley, Martin SneadAbstract:Purpose To present the extent and site of lesion of auditory dysfunction in a large cohort of individuals with type 2 Stickler Syndrome. Type 2 Stickler Syndrome results from a mutation in the gene coding for α-1 type XI pro-collagen, which has been identified in the human vitreous, cartilage and the cochlea of the mouse. The condition is characterised by classic ocular abnormalities, auditory dysfunction, osteoarthropathy and oro-facial dysplasia. Methods This is a population study which used a combination of audiometric, tympanometric, and self-report measures on a series of 65 individuals (mean age 29.2 years, range 3–70, female 63.1%) with genetically confirmed type 2 Stickler Syndrome. Results Hearing impairment was identified in at least one ear for 69% of individuals. Analysis against age-matched normative data showed that reduced hearing sensitivity was present across all test frequencies. Sensorineural hearing loss was most common (77% of ears), with conductive (3%), mixed (7%) and no hearing loss (13%), respectively. The proportion of hypermobile tympanic membranes (24%) was less than previously documented in type 1 Stickler Syndrome. When present, this appears to arise as a direct result of collagen abnormalities in the middle ear. Self-report measures of speech and spatial hearing in sound were comparable to a non-syndromic cohort with similar audiometric thresholds. Conclusions Auditory impairment in type 2 Stickler Syndrome is predominantly associated with cochlear hearing loss of varying severities across affected individuals. The impact on hearing thresholds can be seen across the frequency range, suggesting a contribution of defective collagen throughout the cochlea. Self-report questionnaires showed that difficulties understanding speech, and spatial information in sound (such as that used for localisation), were worse than a young, normal-hearing population but comparable to a non-syndromic cohort with similar audiometric thresholds. Therefore, it is likely that hearing loss in type 2 Stickler Syndrome arises in the auditory periphery, without significant central processing deficits.
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inherited and de novo biallelic pathogenic variants in col11a1 result in type 2 Stickler Syndrome with severe hearing loss
Molecular Genetics & Genomic Medicine, 2020Co-Authors: Annie Mcninch, A J Richards, Thomas R. W. Nixon, Stephen Abbs, Philip Alexander, Adrian Lomas, Pradeep VasudevanAbstract:Background Type 2 Stickler Syndrome is usually a dominant disorder resulting from pathogenic variants in COL11A1 encoding the alpha 1 chain of type XI collagen. Typical molecular changes result in either substitution of an obligate glycine within the Gly-Xaa-Yaa amino acid sequence repeat region of the molecule, mRNA missplicing or deletions/duplications that typically leaves the message in-frame. Clinical features include myopia, retinal detachment, craniofacial, joint, and hearing problems. Fibrochondrogenesis is also a COL11A1 related disorder, but here disease-associated variants are recessive and may be either null alleles or substitutions of glycine, and the condition is usually lethal in infancy. Methods The patient was assessed in the NHS England Stickler Syndrome diagnostic service. DNA from the patient and family were analyzed with Next Generation Sequencing on a panel of genes known to cause Stickler Syndrome. The effect of sequence variants was assessed using minigene analysis. Allele-specific RT-PCR was performed. Results This patient had clinical type 2 Stickler Syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. We identified a de novo in frame deletion of COL11A1 (c.4109_4126del) consistent with dominantly inherited Stickler Syndrome but also a second inherited variant (c.1245+2T>C), on the other allele, affecting normal splicing of COL11A1 exon 9. Conclusion Exon 9 of COL11A1 is alternatively expressed and disease causing changes affecting only this exon modify the phenotype resulting from biallelic COL11A1 disease-associated variants and, instead of fibrochondrogenesis, produce a form of Stickler Syndrome with severe hearing loss. Disease phenotypes from de novo pathogenic variants can be modified by inherited recessive variants on the other allele. This highlights the need for functional and family analysis to confirm the mode of inheritance in COL11A1-related disorders, particularly for those variants that may alter normal pre-mRNA splicing.
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Bone morphogenetic protein 4 (BMP4) loss-of-function variant associated with autosomal dominant Stickler Syndrome and renal dysplasia
European Journal of Human Genetics, 2019Co-Authors: Thomas R. W. Nixon, Allan Richards, Annie Mcninch, Laura K. Towns, Gavin Fuller, Stephen Abbs, Philip Alexander, Richard N. Sandford, Martin P. SneadAbstract:Stickler Syndrome is a genetic disorder that can lead to joint problems, hearing difficulties and retinal detachment. Genes encoding collagen types II, IX and XI are usually responsible, but some families have no causal variant identified. We investigate a variant in the gene encoding growth factor BMP4 in a family with Stickler Syndrome with associated renal dysplasia. Next generation sequencing of the coding region of COL2A1 , COL11A1 and a panel of genes associated with congenital anomalies of the kidney and urinary tract (CAKUT) was performed. A novel heterozygous BMP4 variant causing a premature stop codon, c. 130G>T, p.(Gly44Ter), which segregated with clinical features of Stickler Syndrome in multiple family members, was identified. No variant affecting gene function was detected in COL2A1 or COL11A1 . Skin fibroblasts were cultured with and without emetine, and the mRNA extracted and analysed by Sanger sequencing to assess whether the change was causing nonsense-mediated decay. Nonsense-mediated decay was not observed from the extracted BMP4 mRNA. BMP4 is a growth factor known to contribute to eye development in animals, and gene variants in humans have been linked to microphthalmia/anophthalmia as well as CAKUT. The variant identified here further demonstrates the importance of BMP4 in eye development. This is the first report of a BMP4 DNA variant causing Stickler Syndrome, and we suggest BMP4 be added to standard diagnostic gene panels for this condition.
Arabella V. Poulson - One of the best experts on this subject based on the ideXlab platform.
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auditory dysfunction in type 2 Stickler Syndrome
European Archives of Oto-rhino-laryngology, 2021Co-Authors: Philip Alexander, Annie Mcninch, A J Richards, Arabella V. Poulson, Gregory S. Fincham, Philip Gomersall, Jack Stancellewis, David M. BaguleyAbstract:To present the extent and site of lesion of auditory dysfunction in a large cohort of individuals with type 2 Stickler Syndrome. Type 2 Stickler Syndrome results from a mutation in the gene coding for α-1 type XI pro-collagen, which has been identified in the human vitreous, cartilage and the cochlea of the mouse. The condition is characterised by classic ocular abnormalities, auditory dysfunction, osteoarthropathy and oro-facial dysplasia. This is a population study which used a combination of audiometric, tympanometric, and self-report measures on a series of 65 individuals (mean age 29.2 years, range 3–70, female 63.1%) with genetically confirmed type 2 Stickler Syndrome. Hearing impairment was identified in at least one ear for 69% of individuals. Analysis against age-matched normative data showed that reduced hearing sensitivity was present across all test frequencies. Sensorineural hearing loss was most common (77% of ears), with conductive (3%), mixed (7%) and no hearing loss (13%), respectively. The proportion of hypermobile tympanic membranes (24%) was less than previously documented in type 1 Stickler Syndrome. When present, this appears to arise as a direct result of collagen abnormalities in the middle ear. Self-report measures of speech and spatial hearing in sound were comparable to a non-syndromic cohort with similar audiometric thresholds. Auditory impairment in type 2 Stickler Syndrome is predominantly associated with cochlear hearing loss of varying severities across affected individuals. The impact on hearing thresholds can be seen across the frequency range, suggesting a contribution of defective collagen throughout the cochlea. Self-report questionnaires showed that difficulties understanding speech, and spatial information in sound (such as that used for localisation), were worse than a young, normal-hearing population but comparable to a non-syndromic cohort with similar audiometric thresholds. Therefore, it is likely that hearing loss in type 2 Stickler Syndrome arises in the auditory periphery, without significant central processing deficits.
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Stickler Syndrome in children a radiological review
Clinical Radiology, 2018Co-Authors: N Mcarthur, Annie Mcninch, A J Richards, Arabella V. Poulson, A Rehm, Nick Shenker, J Tanner, M P Snead, P W P BearcroftAbstract:Aim To review the radiological findings of the largest cohort to date of paediatric patients with Stickler Syndrome, all with confirmed molecular genetic analysis and sub-typing. Patients and methods It is understood that the National Health Service (NHS) commissioned service at Addenbrookes Hospital, Cambridge, UK has the largest cohort of Stickler Syndrome patients in the paediatric age group worldwide with 240 registered children. Fifty-nine were assessed radiologically and for their genotypes. These radiographs were reviewed and 74 knee, 45 pelvic, and 47 spinal examinations were evaluated. Results Radiological features were noted in 45.9% of knee radiographs, 11.1% of pelvic radiographs, and 42.6% of spinal radiographs. The findings were reviewed in the light of each patient's specific genetic Stickler Syndrome subtype. Conclusion The prevalence of orthopaedic abnormalities overall in the present series is substantially below those published in previous smaller case series. This would support the more recent findings of an array of ocular only phenotypes of Stickler Syndrome described in the literature.
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prevention of retinal detachment in Stickler Syndrome the cambridge prophylactic cryotherapy protocol
Ophthalmology, 2014Co-Authors: Gregory S. Fincham, Annie Mcninch, A J Richards, Arabella V. Poulson, J D Scott, Laura Pasea, Christopher Carroll, M P SneadAbstract:Purpose: The Stickler Syndromes are the most common causes of inherited and childhood retinal detachment; however, no consensus exists regarding the effectiveness of prophylactic intervention. We evaluate the long-term safety and efficacy of the Cambridge prophylactic cryotherapy protocol, a standardized retinal prophylactic treatment developed to prevent retinal detachment arising from giant retinal tears in type 1 Stickler Syndrome. Design: Retrospective comparative case series. Participants: Four hundred eighty seven patients with type 1 Stickler Syndrome. Methods: Time to retinal detachment was compared between patients who received bilateral prophylaxis and untreated controls, with and without individual patient matching. Patients receiving unilateral prophylaxis (after fellow eye retinal detachment) were similarly compared with an appropriate control subgroup. Individual patient matching ensured equal age and follow-up between groups and that an appropriate control (who had not suffered a retinal detachment before the age at which their individually matched treatment patient underwent prophylactic treatment) was selected. Matching was blinded to outcome events. Individual patient matching protocols purposely weighted bias against the effectiveness of treatment. All treatment side effects are reported. Main Outcome Measures: Time to retinal detachment and side effects occurring after prophylactic treatment. Results: The bilateral control group (n ¼ 194) had a 7.4-fold increased risk of retinal detachment compared to the bilateral prophylaxis group (n ¼ 229) (hazard ratio [HR], 7.40; 95% confi dence interval [CI], 4.53e12.08; P<0.001); the matched bilateral control group (n ¼ 165) had a 5.0-fold increased risk compared to the matched bilateral prophylaxis group (n ¼ 165) (HR, 4.97; 95% CI, 2.82e8.78; P<0.001). The unilateral control group (n ¼ 104) had a 10.3-fold increased risk of retinal detachment compared to the unilateral prophylaxis group (n ¼ 64) (HR, 10.29; 95% CI, 4.96e21.36; P<0.001); the matched unilateral control group (n ¼ 39) had a 8.4-fold increased risk compared to the matched unilateral prophylaxis group (n ¼ 39) (HR, 8.36; 95% CI, 3.24e21.57; P<0.001). No significant long-term side effects occurred. Conclusions: In the largest global cohort of type 1 Stickler Syndrome patients published, all analyses indicate that the Cambridge prophylactic cryotherapy protocol is safe and markedly reduces the risk of retinal detachment. Ophthalmology 2014;121:1588-1597 a 2014 by the American Academy of Ophthalmology.
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alternative splicing modifies the effect of mutations in col11a1 and results in recessive type 2 Stickler Syndrome with profound hearing loss
Journal of Medical Genetics, 2013Co-Authors: A J Richards, John D. Scott, Annie Mcninch, Arabella V. Poulson, Gregory S. Fincham, David A Hill, Bruce Castle, Melissa Lees, Anthony T Moore, M P SneadAbstract:Background Stickler Syndromes types 1, 2 and 3 are usually dominant disorders caused by mutations in the genes COL2A1 , COL11A1 and COL11A2 that encode the fibrillar collagens types II and XI present in cartilage and vitreous. Rare recessive forms of Stickler Syndrome exist that are due to mutations in genes encoding type IX collagen ( COL9A1 type 4 Stickler Syndrome and COL9A2 type 5 Stickler Syndrome). Recently, recessive mutations in the COL11A1 gene have been demonstrated to result in fibrochondrogenesis, a much more severe skeletal dysplasia, which is often lethal. Here we demonstrate that some mutations in COL11A1 are recessive, modified by alternative splicing and result in type 2 Stickler Syndrome rather than fibrochondrogenesis. Methods Patients referred to the national Stickler Syndrome diagnostic service for England, UK were assessed clinically and subsequently sequenced for mutations in COL11A1 . Additional in silico and functional studies to assess the effect of sequence variants on pre-mRNA processing and collagen structure were performed. Results In three different families, heterozygous COL11A1 biallelic null, null/missense or silent/missense mutations, were found. They resulted in a recessive form of type 2 Stickler Syndrome characterised by particularly profound hearing loss and are clinically distinct from the recessive types 4 and 5 variants of Stickler Syndrome. One mutant allele in each family is capable of synthesising a normal α1(XI) procollagen molecule, via variable pre-mRNA processing. Conclusion This new variant has important implications for molecular diagnosis and counselling families with type 2 Stickler Syndrome.
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the efficacy and safety of prophylactic cryotherapy in preventing retinal detachment in type 1 Stickler Syndrome
Investigative Ophthalmology & Visual Science, 2013Co-Authors: Gregory S. Fincham, Annie Mcninch, A J Richards, Arabella V. Poulson, Laura Pasea, Christopher Carroll, J P Scott, M P SneadAbstract:BODY: The efficacy and safety of prophylactic cryotherapy in preventing retinal detachment in type 1 Stickler Syndrome Purpose: To evaluate the efficacy and safety of 360° prophylactic cryotherapy (360PC) according to a standardized protocol and rationale in preventing retinal detachment (RD) in type 1 Stickler Syndrome patients. Methods: A retrospective cohort study. Four hundred and eighty seven type 1 Stickler Syndrome patients with both eyes available for study were allocated to a prophylaxis group according to a standardized protocol and rationale (bilateral 360PC) and compared to a control group (no 360PC), or a mixed group (unilateral RD with subsequent unilateral 360PC) and compared to a mixed-control group (unilateral or bilateral RDs with no 360PC) by adjusted multivariant Cox regression and age-matching analyses. All eyes from all patients were also analysed individually to compare the risk of RD with and without prophylaxis, in addition to randomly selecting one eye from each patient for repeated comparison. The main outcome measures were time to RD (including failure of 360PC requiring retinopexy with or without surgery) and side effects resulting from prophylactic treatment. Results: The control group (n=194) had a greater than seven-fold increased risk of RD compared to the prophylaxis group (n=229) (hazard ratio [HR] = 7.4; 95% confidence interval [CI]: 4.5 – 12.1), with the age-matched control group (n=165) having a five-fold increased risk compared to the age-matched prophylaxis group (n=165) (HR = 5.0; 95% CI: 2.8 – 8.8). Similarly, the mixed-control group (n=104) had a greater than ten-fold increased risk of RD compared to the mixed group (n=64) (HR = 10.3; 95% CI: 5.0 – 21.4), with the age-matched mixed-control group (n=39) having a greater than eight-fold increased risk compared to the age-matched mixed group (n=39) (HR = 8.4; 95% CI: 3.3 – 21.6). Analysis of all individually analysed eyes that received no prophylaxis (n=452) indicated a greater than eleven-fold increased risk of RD compared to those that received 360PC (n=522) (HR = 11.7; 95% CI: 7.9 – 17.2), with a greater than fifteen-fold increased risk calculated when one eye from each patient was randomly selected (HR = 15.4; 95% CI 8.1 – 29.3). Reported side effects from prophylactic treatment were minor and shortlived. Conclusions: All analyses indicate that prophylactic retinopexy delivered according to this standardized protocol is safe and markedly reduces the risk of retinal detachment in type 1 Stickler Syndrome.
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Bone morphogenetic protein 4 (BMP4) loss-of-function variant associated with autosomal dominant Stickler Syndrome and renal dysplasia
European Journal of Human Genetics, 2019Co-Authors: Thomas R. W. Nixon, Allan Richards, Annie Mcninch, Laura K. Towns, Gavin Fuller, Stephen Abbs, Philip Alexander, Richard N. Sandford, Martin P. SneadAbstract:Stickler Syndrome is a genetic disorder that can lead to joint problems, hearing difficulties and retinal detachment. Genes encoding collagen types II, IX and XI are usually responsible, but some families have no causal variant identified. We investigate a variant in the gene encoding growth factor BMP4 in a family with Stickler Syndrome with associated renal dysplasia. Next generation sequencing of the coding region of COL2A1 , COL11A1 and a panel of genes associated with congenital anomalies of the kidney and urinary tract (CAKUT) was performed. A novel heterozygous BMP4 variant causing a premature stop codon, c. 130G>T, p.(Gly44Ter), which segregated with clinical features of Stickler Syndrome in multiple family members, was identified. No variant affecting gene function was detected in COL2A1 or COL11A1 . Skin fibroblasts were cultured with and without emetine, and the mRNA extracted and analysed by Sanger sequencing to assess whether the change was causing nonsense-mediated decay. Nonsense-mediated decay was not observed from the extracted BMP4 mRNA. BMP4 is a growth factor known to contribute to eye development in animals, and gene variants in humans have been linked to microphthalmia/anophthalmia as well as CAKUT. The variant identified here further demonstrates the importance of BMP4 in eye development. This is the first report of a BMP4 DNA variant causing Stickler Syndrome, and we suggest BMP4 be added to standard diagnostic gene panels for this condition.
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Deletions within COL11A1 in Type 2 Stickler Syndrome detected by multiplex ligation-dependent probe amplification (MLPA)
BMC medical genetics, 2013Co-Authors: Raymon Vijzelaar, Martin P. Snead, Sarah Waller, Abdellatif Errami, Alan Donaldson, Teresa Lourenco, Marcia Rodrigues, Vivienne Mcconnell, Gregory S. Fincham, Allan J. RichardsAbstract:COL11A1 is a large complex gene around 250 kb in length and consisting of 68 exons. Pathogenic mutations in the gene can result in Stickler Syndrome, Marshall Syndrome or Fibrochondrogenesis. Many of the mutations resulting in either Stickler or Marshall Syndrome alter splice sites and result in exon skipping, which because of the exon structure of collagen genes usually leaves the message in-frame. The mutant protein then exerts a dominant negative effect as it co-assembles with other collagen gene products. To date only one large deletion of 40 kb in the COL11A1, which was detected by RT-PCR, has been characterized. However, commonly used screening protocols, utilizing genomic amplification and exon sequencing, are unlikely to detect such large deletions. Consequently the frequency of this type of mutation is unknown. We have used Multiplex Ligation-Dependent Probe Amplification (MLPA) in conjunction with exon amplification and sequencing, to analyze patients with clinical features of Stickler Syndrome, and have detected six novel deletions that were not found by exon sequencing alone. Exon deletions appear to represent a significant proportion of type 2 Stickler Syndrome. This observation was previously unknown and so diagnostic screening of COL11A1 should include assays capable of detecting both large and small deletions, in addition to exon sequencing.
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Missense and silent mutations in COL2A1 result in Stickler Syndrome but via different molecular mechanisms
Human mutation, 2007Co-Authors: Allan J. Richards, Maureen Laidlaw, Sarah P Meredith, Pallavi Shankar, Arabella V. Poulson, J D Scott, Martin P. SneadAbstract:Stickler Syndrome due to mutations in COL2A1 is usually the result of premature termination codons and nonsense mediated decay resulting in haploinsufficiency of type II collagen. Here we present two missense mutations and one apparently silent mutation that each result in Stickler Syndrome, but via different molecular mechanisms. One alters the translation initiating ATG codon. The second mutation is a unique glycine substitution in the minor collagen helix of the procollagen. To our knowledge a glycine substitution has not previously been reported in this region of fibrillar procollagens. The third mutation appears to be a silent change altering a GGC codon to GGT both for glycine, but use of a splicing reporter assay demonstrates that it results in missplicing and a shift in the reading frame.
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Stickler Syndrome: further mutations in COL11A1 and evidence for additional locus heterogeneity.
European journal of human genetics : EJHG, 1999Co-Authors: Sam Martin, Allan J. Richards, John R.w. Yates, John D. Scott, Michael Pope, Martin P. SneadAbstract:Stickler Syndrome (hereditary arthro-ophthalmopathy) is a dominantly inherited connective tissue disorder with ocular, oro-facial, auditory and skeletal manifestations. It is genetically and phenotypically heterogeneous with the majority of families having mutations in the gene encoding type II collagen (COL2A1) and exhibiting a characteristic ‘membranous’ or type 1 vitreous phenotype. More recently a novel mutation in the gene encoding the α1 chain of type XI collagen (COL11A1) was reported in a Stickler Syndrome pedigree with a different ‘beaded’ or type 2 vitreous phenotype. In the present study five more families with the type 2 vitreous phenotype were examined for linkage to four candidate genes: COL2A1, COL5A2, COL11A1 and COL11A2. Two families were linked to COL11A1 and sequencing identified mutations resulting in shortened α1(XI) collagen chains, one via exon skipping and the other via a multiexon deletion. One of the families showed weak linkage to COL5A2 but sequencing the open reading frame failed to identify a mutation. In the remaining two families all four loci were excluded by linkage analysis. These data confirm that mutations in COL11A1 cause Stickler Syndrome with the type 2 vitreous phenotype and also reveal further locus heterogeneity.
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Clinical and molecular genetics of Stickler Syndrome
Journal of medical genetics, 1999Co-Authors: Martin P. Snead, John R. YatesAbstract:Stickler Syndrome is an autosomal dominant disorder with characteristic ophthalmological and orofacial features, deafness, and arthritis. Abnormalities of vitreous gel architecture are a pathognomonic feature, usually associated with high myopia which is congenital and non-progressive. There is a substantial risk of retinal detachment. Less common ophthalmological features include paravascular pigmented lattice degeneration and cataracts. Non-ocular features show great variation in expression. Children with Stickler Syndrome typically have a flat midface with depressed nasal bridge, short nose, anteverted nares, and micrognathia. These features can become less pronounced with age. Midline clefting, if present, ranges in severity from a cleft of the soft palate to Pierre-Robin sequence. There is joint hypermobility which declines with age. Osteoarthritis develops typically in the third or fourth decade. Mild spondyloepiphyseal dysplasia is often apparent radiologically. Sensorineural deafness with high tone loss may be asymptomatic or mild. Occasional findings include slender extremities and long fingers. Stature and intellect are usually normal. Mitral valve prolapse was reported to be a common finding in one series but not in our experience. The majority of families with Stickler Syndrome have mutations in the COL2A1 gene and show the characteristic type 1 vitreous phenotype. The remainder with the type 2 vitreous phenotype have mutations in COL11A1 or other loci yet to be identified. Mutations in COL11A2 can give rise to a Syndrome with the systemic features of Stickler Syndrome but no ophthalmological abnormality.
