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.     

Acquired haemophilia B: a case report and literature review

Acquired haemophilia is a rare disease; it occurs most frequently in elderly patients. The majority of cases are due to autoantibodies to factor VIII, which deplete circulating factor VIII or acquired haemophilia A. Only few cases of acquired haemophilia B are reported until today. We report a case of a 7-year-old girl with no past medical history of bleeding disorder and who present an extensive haematoma in the left calf. The diagnosis was established by the demonstration of an isolated prolongation of the activated partial thromboplastin time (APTT) with a reduced factor IX level and evidence of factor IX inhibitor activity to 2 Bethesda Unit (2UB). Diagnosis of acquired haemophilia B confirmed, patient received recombinant factor VIIa and corticosteroid treatment. Bleeding symptoms had completely disappeared and coagulation tests become normal. In conclusion, if bleeding symptoms are associated with unexplained prolongation of APTT, an inhibitor against factor must be searched for not missing an acquired coagulation disease.     

Peripheral neuropathies associated with primary Sjögren syndrome: immunologic profiles of nonataxic sensory neuropathy and sensorimotor neuropathy

We conducted this study to characterize the relationship between primary Sj?gren syndrome (pSS)-associated peripheral neuropathy (PN) and markers of B-cell monoclonal proliferation and chronic activation. The cohort included 120 consecutive patients presenting with definite pSS according to the American-European Consensus Group criteria. Serum markers of chronic B-cell activation included autoantibodies and hypergammaglobulinemia. Markers of monoclonal B-cell proliferation included mixed cryoglobulin, monoclonal gammopathy, abnormal κ/λ free light chain (FLC) ratio, and B-cell non-Hodgkin lymphoma (B-NHL). Definite PN was present in 30 patients (25%) including 7 patients (23%) with sensorimotor neuropathy, 3 patients (10%) with ataxic sensory neuropathy, and 20 patients (67%) with nonataxic sensory neuropathy. Patients with a sensorimotor neuropathy differed from those without PN by higher rates of monoclonal B-cell proliferation markers, that is, mixed cryoglobulin (57% vs. 11%; p = 0.008), monoclonal gammopathy (71% vs. 17%; p = 0.004), higher FLC ratio (2.7 ± 1.5 vs. 1.7 ± 1.8; p = 0.024), and B-NHL (57% vs. 3%; p < 0.001). Patients with nonataxic sensory neuropathy were characterized by a higher age (57.5 ± 10.7 vs. 48.7 ± 14.3 years; p = 0.007), more frequent central nervous system (CNS) involvement (15% vs. 2%; p = 0.04) and a lower prevalence of chronic B-cell activation serum markers, that is, antinuclear antibodies (ANA) (60% vs. 90%; p = 0.003), anti-SSA (Ro) (40% vs. 72%; p = 0.009), anti-SSB (La) (15% vs. 41%; p = 0.039), rheumatoid factor (37% vs. 67%; p = 0.02), and hypergammaglobulinemia (35% vs. 64%; p = 0.023). In multivariate analysis, sensorimotor neuropathy was associated with the presence of B-NHL (odds ratio [OR], 39.0; p < 0.001), whereas nonataxic sensory neuropathy was associated with the presence of CNS involvement (OR, 17.0; p = 0.025) and ANA (OR, 0.07; p < 0.001). In conclusion, we found that up to 25% of pSS patients presented with PN, predominantly sensory neuropathy. Distinctive immunologic profiles were found according to the type of SS-associated neuropathy: nonataxic sensory neuropathy was marked by a low prevalence of B-cell activation markers, and sensorimotor neuropathy was marked by a high prevalence of B-cell monoclonal proliferation markers.     

Giant cell tumour of a phalanx in the foot: a case report

Giant cell tumours are uncommon benign osseous neoplasias with an obscure origin. They mostly occur in the epiphyses of long bones after skeletal maturity. Phalangeal bones are a very rare primary site of involvement. The authors report a case of giant cell tumour involving a phalangeal bone in the foot and review the presentation, distinctive features and treatment of this tumour when occurring in this location. A 28-year-old female patient was seen with an aggressive giant cell tumour of the first phalangeal bone of the third ray of her left foot. En bloc resection of the third ray was performed without bone grafting. The patient has now been free from disease for 12 years. When giant cell tumour occurs in such a location, it appears to represent a distinct, more aggressive form of tumour. Because of the higher risks for local recurrence, treatment should be aggressive.     

A c.3216_3217delGA mutation in AGL gene in Tunisian patients with a glycogen storage disease type III: evidence of a founder effect

Mili A, Ben Charfeddine I, Amara A, MamaÏ O, Adala L, Ben Lazereg T, Bougulia J, Saad A, Limem K, Gribaa M. A c.3216_3217delGA mutation in AGL gene in Tunisian patients with a glycogen storage disease type III: evidence of a founder effect. Glycogen storage disease type III (GSD III) is an autosomal recessive disorder characterized by excessive accumulation of abnormal glycogen in the liver and muscles and caused by deficiency in the glycogen debranching enzyme, the amylo‐1,6‐glucosidase (AGL). In this study, we report the clinical, biochemical and genotyping features of five unrelated GSD III patients coming from the same region in Tunisia. The concentration of erythrocyte glycogen and AGL activity were measured by colorimetric and fluorimetric methods, respectively. Four CA/TG microsatellite markers flanking the AGL gene in chromosome 1 were amplified with fluoresceinated primers. The full coding exons and their relevant exon–intron boundaries of the AGL gene were directly sequenced for the patients and their parents. All patients showed a striking increase of erythrocytes glycogen content. No AGL activity was detected in peripheral leukocytes. Sequencing of the AGL gene identified a c.3216_3217delGA (p.Glu1072AspfsX36) mutation in the five patients which leads to a premature termination, abolishing the AGL activity. Haplotype analysis showed that the mutation was associated with a common homozygote haplotype. Our results suggested the existence of a founder effect responsible for GSD III in this region of Tunisia.