Marinesco-Sjögren syndrome in a male with mild dysmorphism

Marinesco-Sjogren syndrome (MSS) is a rare, autosomal recessive disorder comprising cataracts, cerebellar ataxia caused by cerebellar hypoplasia, mild to moderate mental retardation, neuromuscular weakness, short stature, hypergonadotrophic hypogonadism, and skeletal anomalies. The syndrome was recently mapped to chromosome 5q31, but there is evidence for genetic heterogeneity, and no gene has been identified. We report a 5-year-old male with cataracts, ataxia, a progressive cerebellar atrophy, developmental delay, seizures, hypotonia, and a sensorimotor neuropathy consistent with many cases of MSS. He also had mild craniofacial dysmorphism consisting of hypertrichosis and synophrys, deep-set eyes with epicanthic folds, a flat philtrum, a high palate, short thumbs, and a wide sandal gap between the first and second toes. Skeletal findings included an increased kyphosis. We reviewed the literature on MSS to determine if craniofacial dysmorphism and the presence of neuropathy and/or myopathy would prove to be diagnostically useful in this phenotypically heterogeneous condition. The majority of cases of MSS do not have craniofacial dysmorphism, but other cases have been reported with features such as ptosis or a myopathic facies that are likely to reflect the underlying myopathic or neuromuscular processes in MSS.     

Homozygosity mapping of Marinesco-Sjögren syndrome to 5q31

Marinesco-Sj?gren syndrome (MSS), first described in 1931, is an autosomal recessive condition characterised by somatic and mental retardation, congenital cataracts and cerebellar ataxia. Progressive myopathy was later reported to be also a cardinal sign of MSS, with myopathic changes on muscle biopsies. Hypergonadotrophic hypogonadism and skeletal deformities related to pronounced hypotonia were also reported. The major differential diagnosis of MSS is the syndrome defined by congenital cataracts, facial dysmorphism and peripheral neuropathy (CCFDN), which is localised to 18qter. Using homozygosity mapping strategy in two large consanguineous families of Turkish and Norwegian origin, respectively, we have identified the MSS locus on chromosome 5q31. LOD score calculation, including the consanguinity loops, gave a maximum value of 2.9 and 5.6 at theta=0 for the Turkish and the Norwegian families, respectively, indicating linkage between the disease and the D5S1995-D5S436 haplotype spanning a 9.3 cM interval. Patients of the two families presented with the strict clinical features of MSS. On the other hand, the study of two smaller French and Italian families, initially diagnosed as presenting an atypical MS syndrome, clearly excluded linkage from both the MSS locus on 5q31 and the CCFDN locus in 18qter. Patients of the two excluded families had all MSS features (but the myopathic changes) plus peripheral neuropathy and optic atrophy, and various combinations of microcornea, hearing impairment, seizures, Type I diabetes, cerebral atrophy and leucoencephalopathy, indicating that only the pure MSS syndrome is a homogeneous genetic entity.     

Novel and recurrent ALDH3A2 mutations in Italian patients with Sjögren–Larsson syndrome

Sjögren–Larsson syndrome (SLS; MIM#270200) is an autosomal recessive neurocutaneous disease caused by mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase (FALDH), a microsomal enzyme that catalyzes the oxidation of medium- and long-chain aliphatic aldehydes to fatty acids. We studied two unrelated Italian SLS patients with ichthyosis, developmental delay, spastic diplegia and brain white matter disease. One patient was homozygous for a novel ALDH3A2 insertion mutation (c.767insA) in exon 5. The other SLS patient was a compound heterozygote for two previously reported mutations: a splice-site mutation (c.471 + 2T > G) in intron 3 and a missense mutation (c.1094C > T; S365L) in exon 7. Analysis of fibroblast RNA by RT-PCR indicated that the splice-site mutation caused skipping of exons 2 and 3. The c.1094C > T mutation, previously associated with two ALDH3A2 haplotypes, was found on a third distinct haplotype in our patient, which indicates that it arose independently in this kindred. These results add to understanding of the genetic basis of SLS and will be useful for DNA diagnosis of this disease.     

Novel mutations and a severe neurological phenotype in Sjögren-Larsson syndrome patients from Iran

Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder characterized by ichthyosis, spasticity and intellectual disability. The disease is caused by mutations in the ALDH3A2 gene that encodes fatty aldehyde dehydrogenase. We describe 7 Iranian SLS patients from 5 unrelated consanguineous families. Sequencing of ALDH3A2 identified 4 novel mutations, including a 26-bp deletion (c.25_50del), small in-frame deletion (c.370_372del; p.G124del), a termination (p.Q35Ter) and a missense mutation (p.Lys211Glu). Bacterial expression of the p.Lys211Glu and p.G124del mutations showed little or no detectable enzyme activity. Three of the patients exhibited an unusual neuro-regressive clinical course associated with seizures, which may reflect the presence of unidentified genetic or environmental modifiers in this consanguineous population. This cohort represents the largest group of Iranian patients with molecularly confirmed SLS and expands the mutational and clinical spectrum of this disease.     

Identification of candidate genes for Sjögren's syndrome using MRL/lpr mouse model of Sjögren's syndrome and cDNA microarray analysis

Sj?gren's syndrome is a chronic autoimmune disease characterized by focal lymphocytic infiltration of lacrimal and salivary glands, but the precise mechanism of this syndrome is poorly understood. To clarify the mechanism of onset and progression of Sj?gren's syndrome, it is necessary to identify Sj?gren's syndrome-related genes. For this purpose, we used MLR/MpJ-lpr/lpr (MRL/lpr) mouse as a model of human secondary Sj?gren's syndrome and analyzed specific mRNA expression pattern in MRL/lpr mouse salivary glands by in-house cDNA microarray. Among arrayed 2304 genes, 13 genes were isolated as highly expressed genes in MRL/lpr mouse salivary gland in comparison with MRL/MpJ-+/+ (MRL/+) mouse tissue. Subsequently, we performed RT-PCR analysis and confirmed the high expression level of nine genes; caspase3, Ly-6C.2, vimentin, Mel-14 antigen, cathepsin B, mpt1, Laptm5, Gnai2 and UCP2. Five of the nine genes have already been identified in patients with Sj?gren's syndrome or mice models of the syndrome, but the remaining four genes; mpt1, Laptm5, Gnai2, and UCP2 have not been reported previously as Sj?gren's syndrome-related genes. Although, further experiments are necessary to examine the relationship between these four genes and Sj?gren's syndrome, our system of mouse model of Sj?gren's syndrome combined with in-house cDNA microarray is suitable for the isolation of Sj?gren's syndrome-related genes.     

Role of salivary IgA in the pathogenesis of Sjögren syndrome

Saliva IgA autoantibodies against M₃ muscarinic acetylcholine receptors (mAChRs) could be a new marker for the diagnosis for Sjögren syndrome (SS) dry mouth. Saliva IgA from dry mouth primary SS (pSS) or secondary SS patients tested by ELISA recognized membrane parotid gland acinar cell antigens and the synthetic 25-mer peptide corresponding to the second extracellular loop of human M₃ mAChRs. Moreover, the IgA fraction was able to inhibit the [³H]QNB binding to parotid acinar membrane mAChRs. In addition, the IgA prevented carbachol stimulation of protein secretion by the parotid gland. As controls, IgA and saliva from women without dry mouth and from normal control subjects gave negative results on ELISA, binding, and biological assays, thus demonstrating the specificity of the reaction. IgA autoantibodies against mAChR may be considered among the immunoglobulin factors implicated in the pathophysiology of the development of pSS dry mouth and could be a new marker for differentiating SS dry mouth from non-SS dry mouth.     

Involvement of aquaporin 5 in Sjögren’s syndrome

Sjögren’s syndrome (SS) is a chronic autoimmune disease with the pathological hallmark of lymphoplasmacytic infiltration of exocrine glands - more specifically salivary and lacrimal glands - resulting in a diminished production of tears and saliva (sicca syndrome). The pathophysiology underscoring the mechanisms of the sicca symptoms in SS has still yet to be unraveled but recent advances have identified a cardinal role of aquaporin-5 (AQP5) as a key player in saliva secretion as well as salivary gland epithelial cell dysregulation. AQP5 expression and localization are significantly altered in salivary glands from patients and mice models of the disease, shedding light on a putative mechanism accounting for diminished salivary flow.Furthermore, aberrant expression and localization of AQP5 protein partners, such as prolactin-inducible protein and ezrin, may account for altered AQP5 localization in salivary glands from patients suffering from SS and are considered as new players in SS development. This review provides an overview of the role of AQP5 in SS salivary gland epithelial cell dysregulation, focusing on its trafficking and protein-protein interactions.     

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

Meckel–Gruber syndrome (MKS, OMIM #249000) is a multiple congenital malformation syndrome that represents the severe end of the ciliopathy phenotypic spectrum. Despite the relatively common occurrence of this syndrome among Arabs, little is known about its genetic architecture in this population. This is a series of 18 Arab families with MKS, who were evaluated clinically and studied using autozygome-guided mutation analysis and exome sequencing. We show that autozygome-guided candidate gene analysis identified the underlying mutation in the majority (n=12, 71%). Exome sequencing revealed a likely pathogenic mutation in three novel candidate MKS disease genes. These include C5orf42, Ellis–van-Creveld disease gene EVC2 and SEC8 (also known as EXOC4), which encodes an exocyst protein with an established role in ciliogenesis. This is the largest and most comprehensive genomic study on MKS in Arabs and the results, in addition to revealing genetic and allelic heterogeneity, suggest that previously reported disease genes and the novel candidates uncovered by this study account for the overwhelming majority of MKS patients in our population.     

Towards inhibition of morbidity and mortality in Sjögren’s syndrome: opportunities and challenges

In recent years considerable progress has been made in our understanding of the immunopathology of primary Sjögren’s syndrome. Several genetic and environmental risk factors as well as cellular and molecular pathways have been identified, providing multiple targets for therapeutic strategies. Establishment of disease activity scores allows careful monitoring of therapeutic strategies and has set the stage for definition of clinical response criteria. Early detection of autoimmune symptoms before the onset of primary Sjögren’s syndrome might trigger early intervention strategies to prevent immunopathology. New studies that indicated a strong association between lymphoid neogenesis and development of lymphoma and extra-glandular manifestations indicate that future therapeutic strategies should perhaps be directed at patients at risk for more severe disease. Several challenges remain, such as dissecting the causes and consequences of several types of IFN signatures or elucidating how viral triggering of the immune system is involved and could be targeted. The biggest challenge may be prevention of dryness since the causes of dryness remain elusive and could include non-immunological ones. In the coming years it will become clear to what extent novel drugs can prevent immunopathology and clinical symptoms like dryness and fatigue.     

X-linked genes exhibit miR6891-5p-regulated skewing in Sjögren’s syndrome

Journal of Molecular Medicine - Many autoimmune diseases exhibit a strikingly increased prevalence in females, with primary Sjögren’s syndrome (pSS) being the most female-predominant...     

Classification criteria and treatment modalities in primary Sjögren’s syndrome

Primary Sjögren’s syndrome is a systemic autoimmune disease, characterized by a lymphocytic exocrinopathy. Oral and ocular dryness, asthenia and pain represent hallmarks of the disease. Systemic manifestations concern a third of patients, including lymphoma in 5% of the patients. The American European Consensus Group classification criteria have been used in current practice and clinical trials since 2002. New classification criteria were recently proposed by the American Congress of Rheumatology. A group of international experts are currently working to reach a new consensus between the American European Consensus Group classification criteria and the American Congress of Rheumatology proposal for disease classification. In addition, international consensus disease activity scores were recently established. Regarding treatment modalities, symptomatic treatments remain the cornerstone of therapy in pSS, but new biologic treatments are currently evaluated.     

Plummer-Vinson syndrome in primary Sjögren syndrome: a case-based review

This study aimed to describe a patient with Sjögren syndrome who developed Plummer-Vinson syndrome, and to review the literature and describe shared aspects of this rare association. A systematic screening of articles was conducted in PubMed/MEDLINE, LILACS, SciELO, Scopus, Web of Science, and Cochrane, dating 1940 to 2020. All the articles included the association between Sjögren syndrome and Plummer-Vinson syndrome. No language restriction was applied. The following terms were used: “Sjögren syndrome” or “sicca syndrome” and “Plummer-Vinson syndrome” or “Paterson-Kelly syndrome.” We performed our analysis by adding our present case, with a total of 4 cases. Three out of four were female (75%), age varied from 56 to 58 years old. In 2 cases, Sjögren syndrome preceded Plummer-Vinson syndrome diagnosis, and in 1 report, Plummer-Vinson syndrome appeared before Sjögren syndrome. Disease duration varied from 7 to 20 years. In two cases, autoantibodies were available, and antinuclear antibodies and anti-Ro/SS-A were positive in both, and anti-La/SS-B in one of them was associated with anti-dsDNA; however, no data regarding lupus was available in the article. Treatment involved iron supplementation in 3/3. Two out of three received parenteral iron supplementation, and in these two cases, mechanical esophageal dilatation was needless. In the other case, an additional endoscopic esophageal dilatation was necessary to receive the oral iron supplement. All 3 cases had a good outcome. This case illustrates a patient with Sjögren syndrome who developed the rare Plummer-Vinson syndrome. In Sjögren syndrome, the presence of iron-deficiency anemia, dysphagia, and weight loss should alert the physician to search for associated Plummer-Vinson syndrome.

     

Neutralization of muscarinic receptor autoantibodies by intravenous immunoglobulin in Sjögren syndrome

Autoantibodies that inhibit M3 muscarinic receptor (M3R)-mediated neurotransmission and cause bladder and bowel dysfunction have been reported in patients with Sj?gren syndrome and belong to a family of functional autoantibodies that includes the thyroid-stimulating hormone receptor antibody present in Graves disease. We have recently reported that antiidiotypic antibodies present in pooled immunoglobulin (Ig) G or IgG from healthy individuals neutralize anti-M3R antibody-mediated inhibition of smooth muscle contraction in vitro. Here we extend these studies to the clinic by examining whether therapeutic doses of intravenous immunoglobulin (IVIG) provided to patients with autoimmune diseases neutralize anti-M3R activity in vivo and improve bladder and bowel symptoms. Three patients with primary Sj?gren syndrome, dermatomyositis, and celiac disease, respectively, all of whom had anti-M3R activity on a functional bladder contractile assay, were provided a single course of IVIG at a dose of 400 mg/kg per day for 5 days. Anti-M3R activity was neutralized at 4 weeks after IVIG infusion, whereas levels of specific autoantibodies (anti-La, anti-Jo-1, and anti-tissue transglutaminase) were unchanged. Bladder and bowel scores revealed variable improvement after IVIG. Neutralization of anti-M3R activity by IVIG in vivo, presumably as a result of antiidiotypic antibodies directed specifically against anti-M3R autoantibodies, provides a clinical correlate of our in vitro findings. This offers a rationale for IVIG as a treatment for parasympathetic dysfunction in patients with autoantibodies inhibiting postganglionic cholinergic neurotransmission. We suggest the presence of a network of naturally occurring antiidiotypic antibodies that regulate the expression of functional autoantibodies against neuronal receptors and ion channels.     

Coexisting thymic and gastric lymphomas of mucosa-associated lymphoid tissues in a patient with Sjögren syndrome

Lymphomas of mucosa-associated lymphoid tissues (MALTomas) arising from the thymus are extremely rare. In this case report, we describe a 36-year-old woman with an 11-year history of Sj?gren syndrome who was found to have a thymic MALToma coexisting with a gastric MALToma. Both tumors shared similar histologic features, showing clusters of centrocytic-like B cells, lymphoepithelial lesions, and prominent plasmacytic differentiation. They also showed the following identical immunohistochemical features: CD20(+), IgA/lambda(+), CD5(-), and CD43(-). Molecular studies using polymerase chain reaction methods revealed monoclonal gene rearrangement of the immunoglobulin heavy chain in the gastric MALToma, but not in the thymic MALToma. The possible pathogenesis of this unusual case is discussed.