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(a) Prophylactic 360° cryoretinopexy in Type 1 Stickler syndrome according to Cambridge Prophylactic protocol. 3 (b) Laser retinopexy to arrest progression of GRT in type 1 Stickler syndrome (no prophylaxis). Reproduced with permission from Snead. 9 GRT, giant retinal tear.
Source publication
The Stickler syndromes are the leading cause of inherited retinal detachment and the most common cause of rhegmatogenous retinal detachment in childhood. The clinical and molecular genetic spectrum of this connective tissue disorder is discussed in this article, emphasising the key role the ophthalmologist has to play in the identification, diagnos...
Citations
... 7 Currently, pathogenic variants in 6 collagentype genes (COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, COL9A3) and !5 non-collagen genes (LRP2, GZF1, BMP4, PLOD3, LOXL3) have been linked to the disease pathogenesis. 8 Known ocular manifestations include congenital myopia, cataract, abnormalities of vitreous gel architecture, and retinal detachment. The gene locus can contribute to the phenotype observed, with type 1 Stickler syndrome pedigrees (COL2A1 pathogenic variant) associated with a high risk of blindness through giant retinal tear and retinal detachment. ...
... Treatment includes assessment by a craniofacial specialist and/or otolaryngologist, an ophthalmologist, a feeding specialist, and physical and occupational therapies. Preventative surgery is effective at prevention of retinal detachment in patients at substantial risk [32,36]. ...
Hereditary connective tissue disorders include more than 200 conditions affecting different organs and tissues, compromising the biological role of the extracellular matrix through interference in the synthesis, development, or secretion of collagen and/or its associated proteins. The clinical phenotype includes multiple signs and symptoms, usually nonspecific but of interest to rheumatologists because of musculoskeletal involvement. The patient´s journey to diagnosis is long, and physicians should include these disorders in their differential diagnoses of diseases with systemic involvement. In this review, insights for the diagnosis and treatment of osteogenesis imperfecta, hypermobility spectrum disorder/Ehlers–Danlos syndrome, Marfan, Loeys–Dietz, and Stickler syndromes are presented.
... 10 The non-ocular subtype COL11A2-related Stickler Syndrome and the autosomal recessive forms of Stickler Syndrome (types [4][5][6][7][8] are rarer and less wellcharacterised. 2,11 Early detection of Stickler Syndromes allows for effective clinical management and treatment to address specific symptoms. Orofacial and musculoskeletal abnormalities, which can result in varying degrees of pain and reduced functional ability, may require corrective surgeries, therapy, and/or pharmacological pain management. ...
... 7 Some patients may also benefit from individualized speech, feeding, language, physical, and occupational therapy. 11 Early detection also enables regular monitoring and prophylactic treatments. Around 40% of individuals with Stickler Syndromes will develop rhegmatogenous retinal detachment, 1,13 which, if not detected early, causes severe vision loss. ...
Purpose
Stickler Syndromes are multisystem collagenopathies affecting 1 in 7500–9000 individuals and are associated with craniofacial, ocular, auditory, and musculoskeletal complications. Prophylactic retinopexy treatment reduces the risk of retinal detachment, emphasising the need for early detection and multidisciplinary referral. This study evaluated knowledge and awareness of Stickler Syndromes among allied health professionals and their perceived needs for targeted education to improve multidisciplinary care.
Methods
A cross-sectional survey was undertaken among audiologists, speech pathologists, optometrists, orthoptists, and physiotherapists in Australia. Survey questions included practitioner demographics, awareness and knowledge of Stickler Syndromes, confidence managing Stickler Syndromes, and perception of multidisciplinary care needs for Stickler Syndromes.
Results
Of 180 healthcare professions who participated (79% female; 78% aged between 25 and 44 years), 55% indicated that they had heard of Stickler Syndrome, and 14% had directly worked with patients known to have Stickler Syndromes. Practitioners who had were either optometrists, orthoptists, or audiologists. The most recognised clinical sign of Stickler Syndromes was retinal detachment (selected by 66% of optometrists and orthoptists and 16% of other professions), but only 41% of optometrists and orthoptists (27% all respondents) selected cryopexy as a potential management strategy. Vitreous anomaly was recognised as a clinical feature by 20% of all respondents. Overall, 69% of allied health professionals did not feel confident managing Stickler Syndromes, and a similar number of practitioners (69%) indicated that they were willing to attend professional development courses for complex conditions such as Stickler Syndromes.
Conclusion
This study provides meaningful insights on awareness and knowledge of Stickler Syndromes among allied healthcare professionals. Targeted clinician education, enhanced communication between healthcare entities, and multidisciplinary care programs can significantly improve the integrated care of Stickler Syndromes leading to better patient outcomes.
... Approximately half of all individuals with PRS have an underlying syndrome, of which SS is the most common 3,15 . The PRS, which includes micrognathia, glossoptosis, upper airway obstruction and frequently cleft palate, is observed in approximately 30% of SS cases 4,7,15 . In SS cases that result from collagen II mutation, facial features can become less prominent in adulthood, whereas those with collagen XI mutations, like the one present, these alterations usually persist but can become milder 4,7 . ...
... The PRS, which includes micrognathia, glossoptosis, upper airway obstruction and frequently cleft palate, is observed in approximately 30% of SS cases 4,7,15 . In SS cases that result from collagen II mutation, facial features can become less prominent in adulthood, whereas those with collagen XI mutations, like the one present, these alterations usually persist but can become milder 4,7 . Cleft palate is described in approximately 45% of Type-1 SS and 28% of Type-2 SS patients 14 . ...
The Stickler syndrome (SS) is a group of hereditary conditions affecting connective tissue, characterized by orofacial, ocular, skeletal and hearing disabilities. Current literature lacks a detailed prenatal phenotype. A 33-year-old, healthy woman without relevant family history, presented on second trimester ultrasound a fetus with increased nuchal fold, macrophtalmia and micrognathia. The amniocenteses results (PCR to exclude trisomies and arrayCGH) were normal. Subsequent ultrasounds revealed craniofacial edema, micrognathia, flat midface and prominent eyeballs and lips. SS suspicion was raised. Postnatal examination revealed craniofacial dysmorphia, bilateral exophthalmos, retrognathism, glossoptosis and posterior cleft palate with COL11A1 gene deletion, confirming type-2 SS.
... Other characteristic features Page 3/9 include musculo-skeletal problems (arthralgia, hypermobility and early onset degenerative arthritis), hearing loss (both conductive and sensorineural), cleft palate and midfacial underdevelopment. 2 It is the most common cause of rhegmatogenous retinal detachment (RD) in children, and the most common heritable cause of retinal detachment. However, SS shows a highly variable phenotype both between and within families with the condition, and its inheritance can be both dominant or recessive through a variety of genes in uencing the coding or assembly of type II, IX and XI collagen 1 as well as BMP4 (ref. ...
Objective
Stickler Syndrome (SS) is associated with eye, joint and orofacial abnormalities. Most cases are dominantly inherited through variants in genes encoding type-II/XI collagen (COL2A1/COL11A1), with patients having up to 78% retinal detachment (RD) risk.¹ More recently, rarer cases of recessive SS have been identified, associated with pathogenic variants of genes encoding type-IX collagen (COL9A1-3), but there is limited published data on patients’ phenotype or RD risk. Our study aimed to investigate the RD risk in recessive SS, primarily to determine whether patients would benefit from prophylactic retinopexy. A secondary objective was to explore patient phenotypes, identifying key features which clinicians should identify, leading to genetic testing and early diagnosis.
Methods
We report 13 cases from 11 families with Type-IX collagen recessive SS, identified from the cohort attending the National Stickler Syndrome Service at Addenbrooke’s Hospital, Cambridge, between 1/1/15–31/12/22. Patients underwent multidisciplinary assessment by ophthalmology, rheumatology and audiology.
Results
6/11 families exhibited previously undescribed genetic variants, and 7 had consanguineous parents. Clinical findings included abnormal vitreous architecture and high myopia. 15.4% of patients developed RD secondary to horseshoe retinal tears, with no cases of bilateral RD or Giant Retinal Tears. No patients had cleft palate, 30.8% had midfacial hypoplasia. Hearing loss was more prevalent (91.7%) than that reported for dominant SS. Arthropathy was uncommon but highly variable in manifestation.
Conclusions
There is currently insufficient evidence to suggest that all patients with recessive Stickler Syndrome require prophylactic retinopexy, and it should only be offered case-by-case according to individual risk assessment.
... Recent studies have shown that approximately 39% of early-onset high myopia may be caused by mutations in genes associated with a number of other inherited eye diseases [21]. For example, mutations in COL2A1 and COL11A1 genes can cause Stickler syndrome [22], mutations in EYS gene cause RP [23], TSPAN12 and FZD4 are common causative genes for FEVR [24], and high myopia is also an early clinical phenotype of inherited retinal diseases such as cone rod dystrophy(CORD) and gyrate atrophy of the choroid and retina(GA). ...
Purpose
To report novel pathogenic variants of X-linked genes in five Chinese families with early-onset high myopia (eoHM) by using whole-exome sequencing and analyzing the phenotypic features.
Methods
5 probands with X-linked recessive related eoHM were collected in Ningxia Eye Hospital from January 2021 to June 2022. The probands and their family members received comprehensive ophthalmic examinations,and DNA was abstracted from patients and family members. Whole-exome sequencing was performed on probands to screen the causative variants, and all suspected pathogenic variants were determined by Sanger sequencing and co-segregation analysis was performed on available family members. The pathogenicity of novel variants was predicted using silico analysis and evaluated according to ACMG guidelines. RT-qPCR was used to detect differences in the relative mRNAs expression of candidate gene in mRNAs available with the proband and family members in the pedigree 2. The relationship between genetic variants and clinical features was analyzed.
Results
All probands were male, and all pedigrees conformed to an X-linked recessive inheritance pattern. They were diagnosed with high myopia at their first visits between 4 and 7 years old. Spherical equivalent ranged between − 6.00D and − 11.00D.The five novel hemizygous variants were found in the probands, containing frameshift deletion variant c.797_801del (p.Val266Alafs*75) of OPN1LW gene in the pedigree 1, nonsense variant c.513G > A (p.Trp171Ter)of RP2 gene in the pedigree 2, missense variant c.98G > T (p.Cys33Phe) of GPR143 gene in the pedigree 3, frameshift deletion variant c.1876_1877del (p.Met626Valfs*22) of FRMD7 gene in the pedigree 4 and inframe deletion variant c.670_ 675del (p.Glu192_ Glu193del) of HMGB3 gene in the pedigree 5. All variants were classified as pathogenic or likely pathogenic by the interpretation principles of HGMD sequence variants and ACMG guidelines. In family 2, RT-qPCR showed that the mRNA expression of RP2 gene was lower in the proband than in other normal family members, indicating that such variant caused an effect on gene function at the mRNA expression level. Further clinical examination showed that pedigrees 1, 2, 3, and 4 were diagnosed as X-linked recessive hereditary eye disease with early-onset high myopia, including quiescent cone dysfunction, retinitis pigmentosa, ocular albinism, and idiopathic congenital nystagmus respectively. The pedigree 5 had eoHM in the right eye and ptosis in both eyes.
Conclusion
In this paper,we are the first to report five novel hemizygous variants in OPN1LW, RP2, GPR143, FRMD7, HMGB3 genes are associated with eoHM. Our study extends the genotypic spectrums for eoHM and better assists ophthalmologists in assessing, diagnosing, and conducting genetic screening for eoHM.
... Частота в популяции 1:7500-10 000 человек. Гендерные различия отсутствуют [2][3][4]. ...
... Согласно данным OMIM [5], выделяют 5 типов синдромов Стиклера, которые представлены в таблице. В течение последних 20 лет в литературе обсуждается вопрос о целесообразности дополнительного выделения подтипов данных заболеваний, основанных на результатах молекулярно-генетического и офтальмологического обследования [2][3][4]. Синдром Стиклера, тип I, OMIM:108300, АД тип наследования. Встречается с частотой 80-90 % среди пациентов с данной патологией [2]. ...
... Через месяц рецидив отслойки сетчатки (выполнена микроинвазивная задняя витрэктомия) и барьерная лазеркоагуляция сетчатки. Результаты офтальмологического обследования в 7 лет: Vis OD sph-8,0 cyl-2,0 ax 20=0, 3 ...
... Major collagen types affected are type II, IX and XI. [125][126][127] It is inherited in an autosomal dominant pattern with the most common defect in the gene COL2A1. The subtypes are based on ocular and systemic features with a specific genetic defect. ...
... Other systemic features include hypermobility and osteoarthritis of the knee, hip and spine. [126,128,130] Diagnosis of the syndrome is mainly clinical, depending on the spectrum of clinical manifestation. Molecular genetic testing can be performed for confirmation of diagnosis. ...
... Molecular genetic testing can be performed for confirmation of diagnosis. [126,128] Management of stickle syndrome includes regular screening for the systemic as well as ocular and auditory features. Early detection with fundus examination, audiometry, and radiographic investigation will help in early definitive and supportive therapy. ...
(SNHL) can have a large impact on the outcome and treatment of pediatric patients. Due to the common co-incidence of ocular manifestations and SNHL in children, both ophthalmologic and hearing loss screening and routine examinations must be conducted to minimize adverse outcomes and worsening of pathology. Early evaluation and diagnosis is imperative for intervention and further development of the patient. Coincidence requires a thorough evaluation that includes a comprehensive history, examination, and diagnostic testing. In this article, a literature review was conducted to analyze the presentations of various diseases and syndromes, such as Alport Syndrome, Waardenburg Syndrome, Norrie Disease, Usher Disease, Stickler Syndrome, Marfan Syndrome, Congenital Rubella, and Hereditary Optic Neuropathies. We divided the various ocular pathologies into anterior and posterior segment presentations and associated systemic findings for better understanding. Additionally, this review aims to include an update on the management of patients with both ocular and hearing loss manifestations.
... К наследственным нарушениям соединительной ткани относится синдром Stickler (артроофтальмопатия) -гетерогенная коллагенопатия, обусловленная мутациями в различных генах, ответственных за синтез и катаболизм коллагена типа II, IX, XI [42]. Известно 10 клинически и генетически различных подгрупп синдрома Stickler, в 80-90% случаев встречается I тип (#108300) с аутосомно-доминантным наследованием и характерными признаками: лицевые дисморфии (уплощенная средняя треть лицевого черепа), сенсорная тугоухость, близорукость, отслоение сетчатки, глаукома, мембранозный тип стекловидного тела, слепота, расщелина твердого нёба, недостаточное развитие челюсти (Pierre Robin sequence), седловидный нос, скелетные аномалии, артропатия и ПМК [43]. ...
... Частота ПМК не изучена. Диагностические критерии синдрома Stickler не разработаны, с помощью фенотипирования и молекулярно-генетического исследования в 95% случаев определяют основную мутацию [42]. ...
Клиническое значение определяемого при эхокардиографическом исследовании пролапса митрального клапана нередко переоценивают или недооценивают. В настоящее время различают несиндромный, или первичный, пролапс митрального клапана, синдромный – при генетических синдромах (Марфана, Элерса – Данло и др.), при болезнях миокарда (миокардиты, кардиомиопатии и др.) и как проявление малых аномалий сердца. В каждом случае пролапса митрального клапана, выявленного при эхокардиографическом исследовании, необходимо определять системные проявления нарушений соединительной ткани, ассоциированные состояния и прогноз. Для выявления возможных генетических синдромов необходимо ориентироваться на разработанные диагностические критерии, при заболеваниях миокарда – диагностировать основное заболевание, сопровождающееся прогибанием створок митрального клапана. В случае отсутствия признаков несиндромного (первичного) пролапса митрального клапана, конкретного генетического синдрома или заболевания миокарда пролапс митрального клапана рассматривают как малую аномалию сердца.
The clinical significance of mitral valve prolapse detected by echocardiography is often overestimated or underestimated. Currently, there are non-syndromic or primary mitral valve prolapse, syndromic – with genetic syndromes (Marfan, Ehlers – Danlo, etc.), with myocardial diseases (myocarditis, cardiomyopathy, etc.) and as a manifestation of minor heart anomalies. In each case of mitral valve prolapse detected by echocardiography, it is necessary to determine the systemic manifestations of connective tissue disorders, associated conditions and prognosis. To identify possible genetic syndromes, it is necessary to focus on the developed diagnostic criteria; in case of myocardial diseases, it is necessary to diagnose the underlying disease, accompanied by deflection of the mitral valve cusps. In the absence of evidence of non-syndromic (primary) mitral valve prolapse, a specific genetic syndrome, or myocardial disease, mitral valve prolapse is considered a minor cardiac anomaly.
... Stickler syndrome is a hereditary connective tissue disorder that is usually caused by pathogenic variants of genes encoding for fibrillar collagens II, IX, and XI, which are found in the vitreous humour as well as hyaline and elastic cartilage. It affects 1 in 7500 to 9000 newborns [1], and it is the leading cause of heritable rhegmatogenous retinal detachment and rhegmatogenous retinal detachment in childhood [2]. ...
... It is likely that haploinsufficiency of type II collagen during development results in the inability to form a normal meshwork in cartilage and the delayed development of skeletal structures, causing congenital musculoskeletal and orofacial abnormalities such as cleft palate and spondyloepiphyseal dysplasia. Patients also present with failure to fuse growth plates, which could be caused by abnormal distribution of type II collagen in the physis [2]. Type II collagen is also present in inner ear structures, the tympanic membrane, and the joints between the bones of the middle ear, and it is responsible for the shape of the tympanic membrane [33]. ...
The Stickler syndromes are a group of genetic connective tissue disorders associated with an increased risk of rhegmatogenous retinal detachment, deafness, cleft palate, and premature arthritis. This review article focuses on the molecular genetics of the autosomal dominant forms of the disease. Pathogenic variants in COL2A1 causing Stickler syndrome usually result in haploinsufficiency of the protein, whereas pathogenic variants of type XI collagen more usually exert dominant negative effects. The severity of the disease phenotype is thus dependent on the location and nature of the mutation, as well as the normal developmental role of the respective protein.
