Morquio A Syndrome‐Associated Mutations: A Review of Alterations in the GALNS Gene and a New Locus‐Specific Database

Morquio A syndrome (mucopolysaccharidosis IVA) is an autosomal recessive disorder that results from deficient activity of the enzyme N‐acetylgalactosamine‐6‐sulfatase (GALNS) due to alterations in the GALNS gene, which causes major skeletal and connective tissue abnormalities and effects on multiple organ systems. The GALNS alterations associated with Morquio A are numerous and heterogeneous, and new alterations are continuously identified. To aid detection and interpretation of GALNS alterations, from previously published research, we provide a comprehensive and up‐to‐date listing of 277 unique GALNS alterations associated with Morquio A identified from 1,091 published GALNS alleles. In agreement with previous findings, most reported GALNS alterations are missense changes and even the most frequent alterations are relatively uncommon. We found that 48% of patients are assessed as homozygous for a GALNS alteration, 39% are assessed as heterozygous for two identified GALNS alterations, and in 13% of patients only one GALNS alteration is detected. We report here the creation of a locus‐specific database for the GALNS gene ( http://galns.mutdb.org/ ) that catalogs all reported alterations in GALNS to date. We highlight the challenges both in alteration detection and genotype–phenotype interpretation caused in part by the heterogeneity of GALNS alterations and provide recommendations for molecular testing of GALNS.     

Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype

Tardive dyskinesia (TD) is an important limiting factor in the use of typical antipsychotic drugs. Genetic variability in the serotonin 2A (5-HT(2A)) receptor may influence risk for TD but the results of prior studies are not confirmatory. The objective of this study was to determine association of T102C and His452Tyr polymorphisms in the 5-HT(2A) receptor gene (HTR(2A)) with TD in a large, multicentre patient sample. The design employed case-control analysis controlling for possible confounders using pooled, original data from published and available unpublished samples and employing logistic regression, analysis of variance and meta-analysis. The study sample consisted of 635 patients with schizophrenia or schizoaffective disorder (256 with TD and 379 without TD) drawn from five research centres, divided into six groups based on population origin. The main outcome measure was association of a categorical diagnosis of TD based on the Research Diagnostic Criteria for TD with HTR(2A) T102C and His452Tyr genotypes and haplotypes. The findings indicate significant association of TD with HTR(2A) T102C genotype (p=0.002) over and above the effect of population group, also when controlling for age and gender (p=0.0008), but not with His452Tyr genotype. The T102C genotype was significantly associated with TD in older (>median age 47 yr, p=0.002) but not younger patients and in patients with non-orofacial (limb-truncal) (p=0.001) but not orofacial TD. By meta-analysis the Mantel-Haenszel (M-H) pooled odds ratio (OR) across all the available data was 1.64. A T102C-His452Tyr haplotype was significantly associated with TD (p=0.0008). These findings confirm that genetic variability in HTR(2A) contributes a small but significant degree of risk for the expression of TD, particularly in older patients and specifically for the non-orofacial (limb-truncal) type. Together with other genetic variants associated with TD the findings could be used to assess risk in patients who are candidates for treatment with typical antipsychotic medications.     

Mitral valve prolapse in psoriatic arthritis

Twenty-five patients with psoriatic arthritis were studied by echocardiography in view of the known association of related seronegative arthropathies with aortic-valve lesions. The study group included 15 men and ten women with a mean age of 46.5 +/- 14.6 years. Twenty-two patients suffered from peripheral disease whereas three also had axial involvement. No aortic-valve lesions were found; however, mitral-valve prolapse (MVP) was detected in 14 patients (56%), nine men and five women. The mean age, mean duration of psoriasis, and mean duration of arthritis were similar in patients with and without MVP. HLA tissue typing, which was done in nine patients with MVP, revealed only one patient with HLA-B27. There was no predominance of any of the typical antigens found in psoriasis (HLA-B13, HLA-Cw6). In a control group of 32 psoriatic patients without arthritis, only two (6.4%) suffered from MVP.     

Sarcoidosis Versus Foreign-Body Granulomas

A 42-year-old man developed a papulonodular exanthema 10 years following an injury from a shell explosion. The differential diagnosis between sarcoid-like, foreign-body granulomas and Boeck's sarcoid was inconclusive by histology, but x-ray spectroanalytic examination revealed silicon particles within the epitheloid cell granulomas.     

Interactive effect of cytochrome P450 17alpha-hydroxylase and dopamine D3 receptor gene polymorphisms on abnormal involuntary movements in chronic schizophrenia.

BACKGROUND: Tardive dyskinesia is a chronic adverse effect of anti psychotic drugs, where association with a polymorphic site in the dopamine D3 receptor gene has been previously reported. Cytochrome P 450 17alpha-hydroxylase activity has been implicated with modulation of central dopamine release as well as neuroprotection. We investigated the association of a T -->C variation in the cytochrome P 450 17alpha-hydroxylase gene with tardive dyskinesia in patients with chronic schizophrenia. METHODS: Cytochrome P 450 17 allele and genotype frequencies were compared between matched schizophrenia patients with (n = 55) or without tardive dyskinesia (n = 58). Interactive effects of cytochrome P 450 17alpha-hydroxylase with the dopamine D3 Ser9Gly polymorphism on abnormal involuntary movements were examined. RESULTS: There was no difference in cytochrome P 450 17alpha-hydroxylase genotype distribution between patients with and without tardive dyskinesia; however, patients carrying the cytochrome P 450 17alpha-hydroxylase A2-A2 genotype and the dopamine D3gly allele had the highest orofacial (p <.04), distal (p <.05), and incapacitation (p <.04) scores on the Abnormal Involuntary Movements Scale. CONCLUSIONS: Schizophrenia patients who carry the dopamine D3gly allele and the cytochrome P 450 17alpha-hydroxylase A2-A2 genotype may be more likely to develop abnormal orofoacial and distal involuntary movements and to be incapacitated by these movements when chronically exposed to classical antipsychotic drugs.     

124. Metastasizing osteosarcoma

Zusammenfassung Die große Mehrzahl der Osteosarkoma entsteht in den Gliedmaßen. Lokalrezidive sind selten. Der Verlauf der Krankheit wird von der hämatogenen Metastasierung bestimmt. Diese kann durch elektive Maßnahmen beeinflußt werden die auf den Hauptsitz nämlich die Lungen gerichtet sind. Radiotherapie und regionäre Chemotherapie werden geprüft. Sehr vorläufige Ergebnisse sind ermutigend. Die Therapie klinisch evidenter Lungenmetastasen ist chirurgisch. Die Ergebnisse in hoch selektierten Fällen sind auffallend gut. Kriterien zur Ausweitung der Indikation sollen bestimmt werden.     

Extraskeletal Ewing''s Sarcoma of the Scalp

A 15-year-old boy had an extraskeletal Ewing's sarcoma arising in the soft tissues of the scalp. The tumor was rapidly growing, subcutaneous mass unattached to the underlying bony structures. Histologic examination revealed a proliferation of primitive-appearing, round to oval cells adopting a lobular configuration. Immunohistochemical studies confirmed the undifferentiated mesenchymal nature of the neoplasm.     

Paget's disease of the breast with underlying carcinoma arising in systemic scleroderma

A case is presented of Paget's disease of the breast with underlying infiltrating carcinoma arising in a 35-year-old woman with systemic scleroderma. The tumor arose in an area of the skin affected by the systemic scleroderma 4 years after the onset of her systemic disease. The possibility of a causal relationship between these two processes is discussed and a brief review of the literature is presented.