Microphthalmia and congenital cataract in two patients with Stickler syndrome type II: a case report.

BACKGROUND: Stickler syndrome (STL) is a collagenopathy caused by pathogenic variants in collagen-coding genes, mainly COL2A1 or COL11A1 associated with Stickler syndrome type 1 (STL1) or type 2 (STL2), respectively. Affected individuals manifest ocular, auditory, articular, and craniofacial findings in varying degrees. Previous literature and case reports describe high variability in clinical findings for patients with STL. With this case report, we broaden the clinical spectrum of the phenotype. MATERIALS AND METHODS: Case report on two members of a family (mother and son) including clinical examination and genetic testing using targeted trio whole exome sequencing (trio-WES). RESULTS: A boy and his mother presented with microphthalmia, congenital cataract, ptosis, and moderate-to-severe sensorineural hearing loss. Trio-WES found a novel heterozygote missense variant, c.4526A>G; p(Gln1509Arg) in COL11A1 in both affected individuals. CONCLUSIONS: We report a previously undescribed phenotype associated with a COL11A1-variant in a mother and son, expanding the spectrum for phenotype-genotype correlation in STL2, presenting with microphthalmia, congenital cataract, and ptosis not normally associated with Stickler syndrome.

Growing up with Marshall syndrome: A case report from infancy to age 12.5 years.

Marshall syndrome is an extremely rare genetic disorder usually diagnosed in infancy with a prevalence of <1 in 1 million. Based on the literature reviewed, this is the first case report to provide a longitudinal history of a child with Marshall syndrome (from birth to age 12.5 years). This longitudinal case report arose in part from desires of this child's parents to share the story of their early fears at her initial diagnosis and compare those to how well she has turned out.

[Marshall syndrome]. / Syndrome de Marshall.

MARSHALL SYNDROME. Marshall syndrome also known as PFAPA syndrome belongs to the group of autoinflammatory diseases. The acronym reflects the main clinical features of the disease: periodic fever, aphthous stomatitis, pharyngitis, and adenitis. It is the most common autoinflammatory disease, beginning between 1 and 5 years of age. There is little or no impact on growth, but the recurrence of febrile seizures can compromise the quality of life of patients. Clinical diagnosis meets positive and exclusion criteria. Putting it correctly allows a reassuring framework of care and avoids many unnecessary antibiotic treatments. Corticosteroid therapy is the reference treatment for the crisis. Tonsillectomy associated with adenoidectomy can be discussed but is not systematically recommended in this pathology, which is generally benign and most often heals spontaneously with age.

SYNDROME DE MARSHALL. Le syndrome de Marshall, aussi connu sous le nom de syndrome PFAPA, appartient au groupe des maladies auto-inflammatoires. L'acronyme reflète les principales caractéristiques cliniques de la maladie : fièvre périodique, aphtes, pharyngite, adénite. Il s'agit de la maladie auto-inflammatoire la plus fréquente, débutant entre 1 et 5 ans. Il n'y a pas ou peu de retentissement sur la croissance, mais la récurrence des accès fébriles peut obérer la qualité de vie des patients. Le diagnostic clinique répond à des critères positifs et d'exclusion. Bien poser celui-ci permet de poser un cadre de prise en charge rassurant pour l'entourage et d'éviter de nombreux traitements antibiotiques inutiles. La corticothérapie est le traitement de référence de la crise. L'amygdalectomie associée à l'adénoïdectomie peut être discutée mais n'est pas recommandée de façon systématique dans cette pathologie en général bénigne et guérissant le plus souvent spontanément avec l'âge.

Acquired cutis laxa type II (Marshall syndrome) in a 3-month-old boy.

Acquired cutis laxa type II (Marshall syndrome) is a post-inflammatory elastolysis occurring in infancy and childhood. It is challenging to treat with very few effective treatment options available. Herein, we describe the case of a 3-month-old boy with acquired cutis laxa type II secondary to a neutrophilic dermatosis. Early treatment of the initial inflammatory phase is essential to reduce the permanent sequelae.

Exon-Trapping Assay Improves Clinical Interpretation of COL11A1 and COL11A2 Intronic Variants in Stickler Syndrome Type 2 and Otospondylomegaepiphyseal Dysplasia.

Stickler syndrome (SS) is a hereditary connective tissue disorder affecting bones, eyes, and hearing. Type 2 SS and the SS variant otospondylomegaepiphyseal dysplasia (OSMED) are caused by deleterious variants in COL11A1 and COL11A2, respectively. In both genes, available database information indicates a high rate of potentially deleterious intronic variants, but published evidence of their biological effect is usually insufficient for a definite clinical interpretation. We report four previously unpublished intronic variants in COL11A1 (c.2241 + 5G>T, c.2809 - 2A>G, c.3168 + 5G>C) and COL11A2 (c.4392 + 1G>A) identified in type 2 SS/OSMED individuals. The pathogenic effect of these variants was first predicted in silico and then investigated by an exon-trapping assay. We demonstrated that all variants can induce exon in-frame deletions, which lead to the synthesis of shorter collagen XI α1 or 2 chains. Lacking residues are located in the α-triple helical region, which has a crucial role in regulating collagen fibrillogenesis. In conclusion, this study suggests that these alternative COL11A1 and COL11A2 transcripts might result in aberrant triple helix collagen. Our approach may help to improve the diagnostic molecular pathway of COL11-related disorders.

Ocular complications and prophylactic strategies in Stickler syndrome: a systematic literature review.

BACKGROUND: Stickler syndrome is a collagenopathy caused by mutations in the genes COL2A1 (STL1) or COL11A1 (STL2). Affected patients manifest ocular, auditory, articular, and craniofacial manifestations in varying degrees. Ocular symptoms include myopia, retinal detachment, cataract, and glaucoma. The aim of this systematic review was to evaluate the prevalence of ocular manifestations and the outcome of prophylactic treatment on reducing the risk of retinal detachment. METHOD: A systematic literature search was performed in the PubMed database. Information on the cross-study prevalence of myopia, retinal detachment, cataract, glaucoma, visual impairment, severity and age of onset of myopia and retinal detachments. Studies that reported on the outcome of prophylactic treatment against a control group were explored. RESULTS: 37 articles with 2324 individual patients were included. Myopia was found in 83% of patients, mostly of a moderate to severe degree. Retinal detachments occurred in 45% of patients. Generally, the first detachment occurred in the second decade of life in STL1 patients and later in STL2. Cataracts were more common in STL2 patients, 59% versus 36% in STL1. Glaucoma (10%) and visual impairment (blind: 6%; vision loss in one eye: 10%) were rare. Three studies reported on the effect of prophylactic treatment being protective. CONCLUSION: Ocular manifestations are common in Stickler patients, but the comparison between studies was difficult because of inconsistencies in diagnostic and inclusion criteria by different studies. Sight-threatening complications such as retinal detachments are common but although prophylactic therapy is reported to be effective in retrospective studies, evidence from randomized trials is missing.

Acquired cutis laxa secondary to Sweet syndrome in a child (Marshall syndrome): A rare case report.

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.

Homozygous variants in AMPD2 and COL11A1 lead to a complex phenotype of pontocerebellar hypoplasia type 9 and Stickler syndrome type 2.

Pontocerebellar hypoplasia type 9 (PCH9) is an autosomal recessive neurodevelopmental disorder caused by pathogenic variants in the AMPD2 gene. We evaluated the son of a consanguineous couple who presented with profound hypotonia and global developmental delay. Other features included sensorineural hearing loss, asymmetric astigmatism, and high myopia. Clinical whole-exome sequence analysis identified a homozygous missense variant in AMPD2 (NM_001257360.1:c.2201C > T, p.[Pro734Leu]) that has not been previously reported. Given the strong phenotypic overlap with PCH9, including the identification of the typical "Figure 8" appearance of the brainstem on neuroimaging, we suspect this variant was causative of the neurodevelopmental disability in this individual. An additional homozygous nonsense variant in COL11A1 (NM_001854.4:c.1168G > T, p.[Glu390Ter]) was identified. Variants in this alternatively spliced region of COL11A1 have been identified to cause an autosomal recessive form of Stickler syndrome type 2 characterized by sensorineural hearing loss and eye abnormalities, but without musculoskeletal abnormalities. The COL11A1 variant likely also contributed to the individual's phenotype, suggesting two potentially relevant genetic findings. This challenging case highlights the importance of detailed phenotypic characterization when interpreting whole exome data.

Audiologic Manifestations of Marshall Syndrome.

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.

A novel dominant COL11A1 mutation in a child with Stickler syndrome type II is associated with recurrent fractures.

This case describes a child with blindness, recurrent low-impact fractures, low bone mass, and intermittent joint pain who was found to have a novel missense mutation in COL11A1, consistent with Stickler syndrome type II. The case illustrates the phenotypic variability of the syndrome, which may include increased fragility in childhood. INTRODUCTION: Stickler syndrome type II is an autosomal dominant disorder caused by mutations in the gene that encodes the type XI collagen chain α1 (COL11A1). Manifestations include craniofacial dysmorphology and ocular abnormalities that may lead to blindness, hearing loss, and skeletal anomalies that range from joint pain and arthritis to scoliosis and hypermobility. METHODS: Herein, we describe a child who carried the presumed diagnosis of osteoporosis-pseudoglioma syndrome because of the combined findings of recurrent low-impact fractures due to low bone mass and blindness. The child also suffered from joint pain but had no facial dysmorphism or hearing loss. RESULTS: Targeted sequencing and deletion analysis of the LRP5, COL1A1, and COL1A2 genes failed to identify any mutations, and whole exome sequence analysis revealed a novel missense mutation (c.3032C>A:p.P1011Q) in COL11A1, consistent with Stickler type II. CONCLUSION: This case highlights the phenotypic variability of Stickler type II, broadens the list of differential diagnosis of increased bone fragility in childhood, and highlights utility of unbiased genetic testing towards establishing the correct diagnosis in children with frequent fractures.

A novel mutation in the COL2A1 gene in a patient with Stickler syndrome type 1: a case report and review of the literature.

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.

A mild form of Stickler syndrome type II caused by mosaicism of COL11A1.

Stickler syndrome, a clinically as well as molecularly heterogeneous connective tissue disorder, is predominantly inherited in an autosomal dominant manner and is considered complete penetrant. Previously, mosaicism in Stickler syndrome has been reported in only a few cases. We describe a child with Stickler syndrome due to a novel splice site mutation in COL11A1. Initially, Sanger sequencing of both parents showed normal test results for the mutation. Due to mild phenotypic traits, the father was tested again using a more sensitive method (NGS), and was found to have low-grade mosaicism in various tissue samples (range 7-22% of the DNA). Therefore, we recommend using sensitive genetic testing when mosaicism is suspected. Furthermore, we support previous suggestions of parental testing even when the parents of an affected patient do not have obvious phenotypic signs of Stickler syndrome.

Congenital keratoglobus with blue sclera in two siblings with overlapping Marshall/Stickler phenotype.

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.

Marshall syndrome in a young child, a reality: Case report.

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.

Cephalometrics in Stickler syndrome: Objectification of the typical facial appearance.

INTRODUCTION: Stickler syndrome is a connective tissue disorder characterized by orofacial, ocular, skeletal and auditory symptoms. The orofacial phenotype mainly consists of midfacial hypoplasia, micrognathia and cleft palate. Large phenotypic variability is evident though. Few studies have tried to substantiate the typical facial appearance in Stickler syndrome patients. METHODS: Molecularly confirmed Stickler patients were invited to undergo cephalometric analysis based on a lateral radiograph in standardized conditions. Angular and linear measurements were performed according to Steiner's and Sassouni's analysis and compared with age- and gender-matched reference values. RESULTS: Thirteen patients aged 10-62y were included, twelve of whom had type 1 Stickler syndrome (COL2A1 mutation) and one type 2 Stickler syndrome (COL11A1 mutation). The position of maxilla and mandible relative to the cranial base was not significantly different from the reference population (S-N-A: p = 0.73, S-N-B: p = 0.43). The mandibular plane and y-axis showed an elevated angle with the cranial base in most patients, although not significant for the total group (S-N to Go-Me: p = 0.20, S-N to S-Gn: p = 0.18). Dental analysis was normal, except for a higher overjet value (p = 0.006) and a higher angle between occlusal plane and Frankfort plane (p = 0.022). CONCLUSION: Cephalometric analysis was not able to thoroughly prove the abnormal facial appearance in Stickler syndrome. The majority of patients had normal dentofacial proportions. The most frequently observed anomaly in our series is a rather short and posteriorly rotated mandible, but clinical variability is high.

[Marshall syndrome: Clinical, radiological and genetical features of a Tunisian family]. / Syndrome de Marshall: Aspects cliniques, radiologiques et génétiques d'une famille tunisienne.

BACKGROUND: Marshall syndrome is a rare autosomal dominant skeletal dysplasia. It associates a particular facial dysmorphism with midface hypoplasia, ocular abnormalities and sensorineural hearing loss. It is caused by heterozygous mutations in COL11A1 gene coding the 1 chain of collagen XI. Stickler syndrome is the principal differential diagnosis of Marshall syndrome. AIM: Clinical and radiological study of Marshall syndrome in a Tunisian family with a linkage study of the COL11A1 gene to this disease. METHODS: We report the clinical and the radiological findings of a Tunisian family including 8 members affected by Marshall syndrome. The linkage of the COL11A1 gene to this disease was tested using the polymorphic microsatellite markers of DNA. RESULTS: A variability of the clinical expression of Marshall syndrome was reported. Specific Marshall phenotype and an overlapping phenotype between the Marshall and Stickler syndromes were observed among the affected members of this family. The ocular manifestations were also heterogeneous. Marshall syndrome's specific radiological signs were found. The linkage study supports the linkage of the abnormal phenotype to the COL11A1 gene. CONCLUSION: There is a variability of the clinical expression among the affected members of the study's family. We will continue searching the causative mutation to establish a clear genotype- phenotype correlation.

A Review and Proposed Approach to the Neutrophilic Dermatoses of Childhood.

Neutrophilic dermatoses (NDs) are inflammatory skin conditions that are not associated with infection. The classification and clinical approach to these conditions in children is poorly described. This review classifies these conditions into five nosological subtypes: Sweet's syndrome, pyoderma gangrenosum, aseptic pustules, neutrophilic urticarial dermatoses, and Marshall's syndrome. In addition, we review the various secondary diseases that need to be excluded in the clinical management of the NDs of childhood, with a focus on the autoinflammatory conditions that the reader may not be familiar with. We propose a practical clinical approach to these disorders.