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Journal of Developmental Biology Aug 2020The autosomal dominant chondrodystrophies, the Stickler type 2 and Marshall syndromes, are characterized by facial abnormalities, vision deficits, hearing loss, and...
The autosomal dominant chondrodystrophies, the Stickler type 2 and Marshall syndromes, are characterized by facial abnormalities, vision deficits, hearing loss, and articular joint issues resulting from mutations in . Zebrafish carry two copies of the gene, designated and . is located on zebrafish chromosome 24 and is located on zebrafish chromosome 2. Expression patterns are distinct for and and is most similar to that is responsible for human autosomal chondrodystrophies and the gene responsible for changes in the chondrodystrophic mouse model . We investigated the function of in craniofacial and axial skeletal development in zebrafish using a knockdown approach. Knockdown revealed abnormalities in Meckel's cartilage, the otoliths, and overall body length. Similar phenotypes were observed using a CRISPR/Cas9 gene-editing approach, although the CRISPR/Cas9 effect was more severe compared to the transient effect of the antisense morpholino oligonucleotide treatment. The results of this study provide evidence that the zebrafish gene for is required for normal development and has similar functions to the mammalian gene. Due to its transparency, external fertilization, the knockdown, and knockout zebrafish model systems can, therefore, contribute to filling the gap in knowledge about early events during vertebrate skeletal development that are not as tenable in mammalian model systems and help us understand -related early developmental events.
PubMed: 32872105
DOI: 10.3390/jdb8030016 -
Annals of Human Genetics Sep 2020We report the clinical findings of 26 individuals from 16 unrelated families carrying variants in the COL2A1 or COL11A1 genes. Using Sanger and next-generation...
We report the clinical findings of 26 individuals from 16 unrelated families carrying variants in the COL2A1 or COL11A1 genes. Using Sanger and next-generation sequencing, 11 different COL2A1 variants (seven novel), were identified in 13 families (19 affected individuals), all diagnosed with Stickler syndrome (STL) type 1. In nine families, the COL2A1 disease-causing variant arose de novo. Phenotypically, we observed myopia (95%) and retinal detachment (47%), joint hyperflexibility (92%), midface retrusion (84%), cleft palate (53%), and various degrees of hearing impairment (50%). One patient had a splenic artery aneurysm. One affected individual carrying pathogenic variant in COL2A1 showed no ocular signs including no evidence of membranous vitreous anomaly. In three families (seven affected individuals), three novel COL11A1 variants were found. The propositus with a de novo variant showed an ultrarare Marshall/STL overlap. In the second family, the only common clinical sign was postlingual progressive sensorineural hearing impairment (DFNA37). Affected individuals from the third family had typical STL2 signs. The spectrum of disease phenotypes associated with COL2A1 or COL11A1 variants continues to expand and includes typical STL and various bone dysplasias, but also nonsyndromic hearing impairment, isolated myopia with or without retinal detachment, and STL phenotype without clinically detectable ocular pathology.
Topics: Adolescent; Adult; Arthritis; Child; Child, Preschool; Collagen Type II; Collagen Type XI; Connective Tissue Diseases; Czech Republic; DNA Mutational Analysis; Female; Hearing Loss, Sensorineural; Humans; Infant; Male; Middle Aged; Pedigree; Phenotype; Retinal Detachment; Young Adult
PubMed: 32427345
DOI: 10.1111/ahg.12386 -
Journal of Cutaneous Pathology Feb 2020Sweet syndrome is rare in the pediatric population and usually responds well to treatment, resolving without sequelae. Marshall syndrome is a rare pediatric skin disease...
Sweet syndrome is rare in the pediatric population and usually responds well to treatment, resolving without sequelae. Marshall syndrome is a rare pediatric skin disease characterized by loss of elastic tissue (cutis laxa) secondary to acquired, localized neutrophilic dermatitis without any internal organ involvement. Only few cases of Marshall syndrome (acquired cutis laxa type II) have been reported. Systemic steroids and dapsone show excellent results in Sweet syndrome. Although there is no satisfactory treatment for cutis laxa, dapsone can be used in the acute phase for control of swelling.
Topics: Cataract; Child, Preschool; Collagen Type XI; Craniofacial Abnormalities; Cutis Laxa; Dapsone; Female; Hearing Loss, Sensorineural; Humans; Osteochondrodysplasias; Sweet Syndrome
PubMed: 31437319
DOI: 10.1111/cup.13567 -
Ceska a Slovenska Oftalmologie :... 2018The authors present the ocular finding in a patient sent to the Department of Paediatric Ophthalmology at the Children's University Hospital - Faculty of Medicine,...
The authors present the ocular finding in a patient sent to the Department of Paediatric Ophthalmology at the Children's University Hospital - Faculty of Medicine, Comenius University in Bratislava at the age of 3 months, with congenital glaucoma in her right eye and bilateral high myopia. The family anamnesis of the patient shows repeated occurrence of stunted growth, myopia, facial dysmorphia and cataract. The child's mother had high myopia, the mother's brother underwent cataract surgery, the child's grandmother and her sisters and the child's great grandmother had high myopia and glaucoma, and probably underwent cataract surgery at a young age. The child's mother and grandmother underwent a genetic examination, with a conclusion of Marshall syndrome. Within the framework of neonatal screening, poor cortical auditory evoked potential, a defect of the interventricular septum and bifid uvula were diagnosed in the child. With regard to the overall finding in the patient and the genetic family history, we suspected Marshall syndrome. A genetic examination determined Stickler syndrome type 1 with the presence of mutation in the COL2A gene (variant c.2710C >T (p.Arg904Cys,rs121912882)). Due to high intraocular pressure with the impossibility of compensation by medication, bilateral trabuculectomy was performed on the patient. At present the patient has intraocular pressure compensated with adjuvant medicamentous therapy. With regard to high myopia and pronounced degenerative changes on the periphery of the retina in the sense of lattice degeneration, preventive cryopexy of the retinal periphery is planned. A molecular genetic analysis helped diagnose the pathology as Stickler syndrome type 1, which manifested phenotype symptoms of Marshall syndrome or Stickler syndrome type 2. Key words: Marshall syndrome, Stickler syndrome, mid-facial dysmorfism, myopia, glaucoma, cataract.
Topics: Arthritis; Connective Tissue Diseases; Female; Hearing Loss, Sensorineural; Humans; Infant; Male; Myopia; Pedigree; Retinal Detachment
PubMed: 30650974
DOI: 10.31348/2018/1/5-3-2018 -
Otology & Neurotology : Official... Sep 2018Marshall syndrome is a genetic disorder caused by mutations in the COL11A1 gene. This syndrome is characterized by skeletal, ophthalmologic, craniofacial, and auditory...
OBJECTIVE
Marshall syndrome is a genetic disorder caused by mutations in the COL11A1 gene. This syndrome is characterized by skeletal, ophthalmologic, craniofacial, and auditory abnormalities. Hearing loss is among the main manifestations reported in this disorder being observed in approximately 80% of affected individuals.The present study aims to describe the audiologic characteristics of three members of a family with Marshall syndrome and also serves as a review of the literature.
STUDY DESIGN
Family study.
SETTING
Tertiary care otology and skull base center.
PATIENTS
We report the audiologic findings in a family with Marshall syndrome consisting of a mother and her son and daughter.
INTERVENTION(S)
The audiologic evaluation included tympanometry, acoustic reflexes testing, auditory brainstem response, transient otoacoustic emissions, pure-tone audiometry, speech audiometry in quiet, and conditioned play audiometry. These methods were applied according to the age of the patients. In addition, we provide a review of the English-language literature in an attempt to clarify the auditory phenotype of this syndrome.
RESULTS
All 3 affected individuals had heterozygous c.3816+1G>A mutation in the splicing donor site of intron 50 of the COL11A1 gene. All three patients in our study had bilateral sensorineural hearing loss. Hearing impairment ranged from mild to moderate in the daughter, moderate in the son, and from mild to moderate in their mother.
CONCLUSION
The majority of individuals with Marshall syndrome present early-onset bilateral sensorineural hearing loss. Hearing impairment is usually detected in early childhood, progresses gradually, and becomes stable in late adulthood, with a severity ranging from mild to severe.
Topics: Acoustic Impedance Tests; Adult; Audiology; Audiometry, Pure-Tone; Audiometry, Speech; Auditory Threshold; Cataract; Child, Preschool; Collagen Type XI; Craniofacial Abnormalities; Evoked Potentials, Auditory, Brain Stem; Female; Hearing Loss, Sensorineural; Humans; Male; Osteochondrodysplasias; Otoacoustic Emissions, Spontaneous
PubMed: 30020262
DOI: 10.1097/MAO.0000000000001896 -
Journal of Medical Case Reports Aug 2017Stickler syndrome is a group of collagenopathies characterized by ophthalmic, skeletal, and orofacial abnormalities, with the degree of symptoms varying among patients.... (Review)
Review
BACKGROUND
Stickler syndrome is a group of collagenopathies characterized by ophthalmic, skeletal, and orofacial abnormalities, with the degree of symptoms varying among patients. Mutations in the COL2A1, COL11A1, and COL11A2 procollagen genes cause Stickler syndrome. Marshall syndrome, caused by a COL11A1 mutation, has clinical overlap with Stickler syndrome.
CASE PRESENTATION
A 2-year-old Japanese boy was presented to our hospital with short stature (79.1 cm, -2.52 standard deviation). His past medical history was significant for soft cleft palate and bilateral cataracts. He had a flat midface, micrognathia, and limitations in bilateral elbow flexion. Radiographs showed mild spondyloepiphyseal dysplasia. Initially, we suspected Marshall syndrome, but no mutation was identified in COL11A1. At 8 years old, his height was 116.2 cm (-1.89 standard deviation), and his orofacial characteristics appeared unremarkable. We analyzed the COL2A1 gene and found a novel heterozygous mutation (c.1142 G > A, p.Gly381Asp).
CONCLUSIONS
In this case report, we identify a novel missense mutation in the COL2A1 gene in a patient with Stickler syndrome type 1, and we describe age-related changes in the clinical phenotype with regard to orofacial characteristics and height. Genetic analysis is helpful for the diagnosis of this clinically variable and genetically heterogeneous disorder.
Topics: Arthritis; Cataract; Child; Child, Preschool; Cleft Palate; Collagen Type II; Collagen Type XI; Connective Tissue Diseases; Craniofacial Abnormalities; Diagnosis, Differential; Growth Disorders; Hearing Loss, Sensorineural; Humans; Male; Micrognathism; Mutation; Osteochondrodysplasias; Palate, Soft; Phenotype; Retinal Detachment
PubMed: 28841907
DOI: 10.1186/s13256-017-1396-y -
Indian Journal of Dermatology,... 2017
Topics: Administration, Topical; Adrenal Cortex Hormones; Adult; Cataract; Collagen Type XI; Craniofacial Abnormalities; Hearing Loss, Sensorineural; Humans; Male; Osteochondrodysplasias
PubMed: 28164888
DOI: 10.4103/0378-6323.198447 -
Indian Journal of Ophthalmology Nov 2016We aimed to describe congenital keratoglobus with blue sclera in two siblings with overlapping Marshall/Stickler phenotype. Two sisters (ages four and six) with...
We aimed to describe congenital keratoglobus with blue sclera in two siblings with overlapping Marshall/Stickler phenotype. Two sisters (ages four and six) with bilateral high astigmatism were evaluated by slit-lamp microscopy. Corneal topography and pachymetry maps were also obtained. Slit-lamp examination revealed that both corneas were globular in shape with peripheral corneal thinning. Pachymetry maps showed diffuse corneal thinning. Two siblings had in common the features of keratoglobus, blue sclera, atypical face, hearing loss, and hypermobile joints. We tentatively diagnosed the sisters as having an overlapping Marshall-Stickler phenotype based on clinical and radiological findings. Marshall-Stickler syndrome may exist in the differential diagnosis of keratoglobus with blue sclera.
Topics: Abnormalities, Multiple; Cataract; Child; Child, Preschool; Collagen Type XI; Cornea; Corneal Topography; Craniofacial Abnormalities; Eye Diseases, Hereditary; Female; Genetic Diseases, X-Linked; Hearing Loss, Sensorineural; Humans; Osteochondrodysplasias; Phenotype; Sclera; Siblings; Visual Acuity
PubMed: 27958215
DOI: 10.4103/0301-4738.195615 -
Medicine Nov 2016Recurrent fever syndrome, known as the Marshall syndrome (MS), is a clinical entity that includes several clinical features, such as: fever (39-40°C) that occurs...
BACKGROUND
Recurrent fever syndrome, known as the Marshall syndrome (MS), is a clinical entity that includes several clinical features, such as: fever (39-40°C) that occurs repeatedly at variable intervals (3-8 weeks) and in episodes of 3 to 6 days, cervical adenopathy, pharyngitis, and aphthous stomatitis. The diagnosis of MS is one of exclusions; laboratory data is nonspecific and no abnormalities correlated with MS have been detected thus far.
METHODS
The authors report the case of a 2-year-old girl admitted to a tertiary pediatric center for repeated episodes of fever with aphthous stomatitis and laterocervical adenopathy.
RESULTS
The child's case history raised the suspicion of MS, which was subsequently confirmed by exclusion of all the other differential diagnoses (recurrent tonsillitis, juvenile idiopathic arthritis, Behçet's disease, cyclic neutropenia, hyperglobulinemia D syndrome). After the 3 febrile episodes, bilateral tonsillectomy was performed based on the parents' consent, with favorable immediate and remote postoperative clinical outcomes. The diagnosis of MS is one based on exclusion, as laboratory data is nonspecific. We took into consideration other causes of recurrent fever (recurrent tonsillitis, infectious diseases, juvenile idiopathic arthritis, Behçet's disease, cyclic neutropenia, Familial Mediterranean fever syndrome, hyperglobulinemia D syndrome). In our case, MS criteria were met through clinical examination and the child's outcome. Subsequently, laboratory data helped us establish the MS diagnosis.
CONCLUSIONS
Pediatricians should consider the MS diagnosis in the context of recurrent fever episodes associated with at least one of the following symptoms: pharyngitis, cervical adenopathy or aphthous stomatitis. Despite the indication for tonsillectomy in young children being controversial, in this case the surgery led to the total remission of the disease.
Topics: Cataract; Child, Preschool; Collagen Type XI; Craniofacial Abnormalities; Female; Hearing Loss, Sensorineural; Humans; Osteochondrodysplasias
PubMed: 27858841
DOI: 10.1097/MD.0000000000005065 -
Joint Bone Spine Jul 2016PFAPA syndrome is the most frequent periodic fever syndrome in non-Mediterranean patients. The pathogenesis is unclear and the treatment is purely symptomatic and not...
INTRODUCTION
PFAPA syndrome is the most frequent periodic fever syndrome in non-Mediterranean patients. The pathogenesis is unclear and the treatment is purely symptomatic and not standardized. The aim of this study was to assess colchicine's efficacy as prophylactic treatment in PFAPA syndrome and to identify factors able to predict response to treatment.
METHODS
We performed a retrospective, multicentric, cohort study of PFAPA patients under colchicine prophylaxis. PFAPA diagnosis was established according to Feder's criteria. Medical records were reviewed and analyzed for demographic, clinical and laboratory data. We distinguished one responder's group, defined as patients who had no more or twice fewer crises under colchicine and another one of non-responders. Subgroup analyses were performed using non-parametric Mann-Whitney test for quantitative data and calculating odds ratio and confidence interval for qualitative data. Difference between the two groups was considered significant for P-value<0.05 or a confidence interval different from 1.
RESULTS-CONCLUSION
Twenty children, 65% of whom were boys, were analyzed. Their mean age at disease onset was 2.3±1.5 years. Among the nine responder patients, five were MEFV (71%) heterozygotes: M694V mutation in four and V726A once. Heterozygous MEFV gene mutation tended to be more frequent in the responders group (71% versus 43%; OR=0.3 [0.03-2.7]). Non-responder patients had more chronic fatigue (82% versus 33%; OR=9 [1,14-71]) and had more oral aphtosis (82% versus 11%; OR=36 [1,7-141]) than the responders ones. Although not significant, colchicine treatment appeared more effective in patients with less complete PFAPA phenotype and MEFV heterozygosity.
Topics: Age Factors; Child, Preschool; Cohort Studies; Colchicine; Confidence Intervals; Female; Hereditary Autoinflammatory Diseases; Humans; Infant; Lymphadenitis; Male; Odds Ratio; Pharyngitis; Prognosis; Retrospective Studies; Risk Assessment; Sex Factors; Statistics, Nonparametric; Stomatitis, Aphthous; Syndrome; Treatment Outcome
PubMed: 27068612
DOI: 10.1016/j.jbspin.2015.08.017