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.

BACKGROUND: Collagen type XI alpha 2 chain is a component of type XI collagen and is expressed in various tissues including articular cartilage and tectorial membrane of the cochlea. Variants in the COL11A2 gene, which encodes collagen type XI alpha 2 chain, has been reported to cause hearing loss and has been associated with osteoarthritis and ossification of the posterior longitudinal ligament of the spine. Despite the importance of type XI collagen in the joints, association of rheumatoid arthritis (RA) with COL11A2 has not been reported.
METHODS: The patient is a 60-year-old female, born to Japanese parents of no known consanguinity. She had progressive hearing loss since childhood. Her father also had progressive hearing loss before middle age. She developed joint pain in the knees and the hips in her forties. When she was 56, she developed polyarthritis. Rheumatoid factor and anti-CCP antibodies were positive.
METHODS: She was diagnosed with osteoarthritis and RA. Whole exome analysis detected 2 rare variants, c.4201C>T, p.(Arg1401Trp) and c4265C>T, p.(Pro1422Leu), in the COL11A2 gene (NM_080680.2). Whole genome analysis with a long insert size confirmed 2 variants that are in trans.
RESULTS: She received a cochlear implant, which improved her hearing. She was treated with methotrexate, golimumab, tocilizumab, and upadacitinib with partial responses for her RA.
CONCLUSIONS: We herein report a patient with RA with compound heterozygous variants in the COL11A2 gene. Autoantibodies against type XI collagen are detected in the sera of patients with RA, suggesting the possibility that type XI collagen may be involved in the pathogenesis of RA as an autoantigen. The hearing loss and osteoarthritis in this patient may be due to the compound heterozygous variants in the COL11A2 gene, and the conformational changes induced by the variants may have changed the immunogenicity of type XI collagen, leading to the development of RA.

Stickler Syndrome is a rare connective tissue disorder, characterized by clinical, and genetic heterogeneity. The clinical expression is highly variable, including moderate to severe myopia in childhood, hearing loss, facial dysmorphic features, cleft palate, and early osteoarthritis. COL2A1, COL11A1, and COL11A2 mutations account of the majority of autosomal dominant Stickler Syndrome and, in particular, a heterozygous mutation in COL11A1 gene is identified in about 10 to 20% of Stickler Syndrome patients.
Herein, we report a case of an 8-year- old child with Stickler Syndrome, presenting with early-onset of myopia with vitreal abnormalities, facial dysmorphic characteristics, and mild hearing loss later in childhood. To identify the underlying genetic cause, Whole Exome Sequencing was carried out for COL11A1 gene.
A novel de novo heterozygous splice site variant (NM_001854: c.1845 + 5G> C) of the COL11A1 gene, which had not been previously reported, was identified by Whole Exome Sequencing.
We reported a novel COL11A1 mutation in a child with Stickler Syndrome presenting a phenotype of early-onset of ocular anomalies and mild hearing loss later in childhood. Our findings confirm the variability of the expression of the disease, even in the contest of the same gene-related disorder, thus, contributing to improve the knowledge on clinical and molecular basis of this rare disease.

Elbow tendinopathy is a common pathology of the upper extremity that impacts both athletes and workers. Some research has examined the genetic component as a risk factor for tendinopathy, mainly in the lower limbs. A case-control study was designed to test for a relationship between certain collagen gene single nucleotide polymorphisms (SNPs) and elbow tendon pathology. A sample of 137 young adult athletes whose sports participation involves loading of the upper limb were examined for the presence of structural abnormalities indicative of pathology in the tendons of the lateral and medial elbow using ultrasound imaging and genotyped for the following SNPs: COL5A1 rs12722, COL11A1 rs3753841, COL11A1 rs1676486, and COL11A2 rs1799907. Anthropometric measurements and data on participants\' elbow pain and dysfunction were collected using the Disabilities of the Arm, Shoulder and Hand and the Mayo Clinic Performance Index for the Elbow questionnaires. Results showed that participants in the structural abnormality group had significantly higher scores in pain and dysfunction. A significant relationship between COL11A1 rs3753841 genotype and elbow tendon pathology was found (p = 0.024), with the CT variant associated with increased risk of pathology.

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.

Inherited eye disorders are genetically determined conditions that are present from birth and usually manifest early, although some may develop later in life. Despite their low incidence, they are a common etiology of pediatric blindness. The occurrence of more than one such disease in a patient is very rare.
Case series of two unrelated patients with simultaneous Stargardt disease (STGD1) as well as Stickler\'s Syndrome (SS), both genetically confirmed.
Patient 1: 13-year-old girl was referred for unexplained bilateral decreased vision for 6 months. She had a clinical diagnosis of SS, same as her mother. Her visual acuity was 20/200 with high myopia in both eyes. Her fundus showed foveal/perifoveal atrophy, retinal pigment epithelium (RPE) changes and beaded vitreous. Goldman visual fields (GVF) revealed enlarged blind spots with central depression. A macular dystrophy was suspected. Genetic testing revealed SS, COL11A1 gene mutation; and STGD1, ABCA4 gene mutation. Patient 2: 67-year-old female with a history of hearing loss, cleft palate, strabismus and myopia, same as her daughter and granddaughters. Her visual acuity was 20/400 and 20/250 with high myopia in both eyes. Her fundus showed macular pigment clumping and RPE atrophy with no vitreous abnormality. GVF revealed a relative central scotoma with generalized constriction. Genetic testing revealed SS, COL11A2 gene mutation; and STGD1, ABCA4 gene mutation.
If a patient\'s signs/symptoms cannot be explained by the working/known diagnosis, additional work up should be pursued for concomitant diseases. SS and STGD1 are commonly diagnosed inherited eye disorders and can coexist in one patient on rare occasions.

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.
METHODS: 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.

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The Stickler syndrome (SS) has been described as a \"hereditary progressive arthro-ophtalmopathy\" by Stickler in 1965, due to mutations on the collagen genes. Currently about 40 different genes have been identified which encode for at least 27 different collagens. The majority of mutations occur in the COL2A1 gene on chromosome 12q13 (SS type I). Mutations in COL11A1 are less frequent (SS type II). More recently, mutations in COL11A2 and in the COL9A1 gene have been reported with particular phenotypes. The main features of this autosomal inherited disease are ocular, auditory with orofacial abnormalities and early-onset osteoarthritis. We report the clinical presentation of an adult and his son, with a particular focus on the bone status of the father, radiography, bone densitometry and transiliac bone biopsy showing that he was suffering from osteoporosis. The lumbar bone mineral density was low with a Z-score at -2.9. Transiliac bone biopsy showed a dramatic decrease of trabecular bone volume (8.6%; Nl: 19.5±4.9%), thin trabeculae and a disorganized trabecular network. A slight increase of osteoid parameters was observed. Bone resorption was markedly increased with an excessive number of active (TRAcP+) osteoclasts. The cortical width was normal, but a slight increase of cortical porosity was found. Osteoporosis has been rarely described in the SS. It might be useful to systematically perform a bone densitometry in all patients with SS and to discuss the indication of a transiliac bone biopsy in severe cases.

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.