scholarly journals Expanding the Nude SCID/CID Phenotype Associated with FOXN1 Homozygous, Compound Heterozygous, or Heterozygous Mutations

2021 ◽  
Author(s):  
Giuliana Giardino ◽  
Svetlana O. Sharapova ◽  
Peter Ciznar ◽  
Fatima Dhalla ◽  
Luca Maragliano ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
Late Onset ◽  
Clinical Manifestations ◽  
Residual Activity ◽  
Compound Heterozygous ◽  
Nail Dystrophy ◽  
Severe Infections ◽  
Heterozygous Patient ◽  
Negative Dominance ◽  
Atypical Phenotype

AbstractHuman nude SCID is a rare autosomal recessive inborn error of immunity (IEI) characterized by congenital athymia, alopecia, and nail dystrophy. Few cases have been reported to date. However, the recent introduction of newborn screening for IEIs and high-throughput sequencing has led to the identification of novel and atypical cases. Moreover, immunological alterations have been recently described in patients carrying heterozygous mutations. The aim of this paper is to describe the extended phenotype associated with FOXN1 homozygous, compound heterozygous, or heterozygous mutations. We collected clinical and laboratory information of a cohort of 11 homozygous, 2 compound heterozygous, and 5 heterozygous patients with recurrent severe infections. All, except one heterozygous patient, had signs of CID or SCID. Nail dystrophy and alopecia, that represent the hallmarks of the syndrome, were not always present, while almost 50% of the patients developed Omenn syndrome. One patient with hypomorphic compound heterozygous mutations had a late-onset atypical phenotype. A SCID-like phenotype was observed in 4 heterozygous patients coming from the same family. A spectrum of clinical manifestations may be associated with different mutations. The severity of the clinical phenotype likely depends on the amount of residual activity of the gene product, as previously observed for other SCID-related genes. The severity of the manifestations in this heterozygous family may suggest a mechanism of negative dominance of the specific mutation or the presence of additional mutations in noncoding regions.

scholarly journals Cobalamin C deficiency presenting with diffuse alveolar hemorrhage and pulmonary microangiopathy: a case series of four patients

2019 ◽  
Author(s):  
Jinrong Liu ◽  
Xiaolei Tang ◽  
Chunju Zhou ◽  
Hui Xu ◽  
Haiming Yang ◽  
...  
Keyword(s):  
Lung Disease ◽  
Late Onset ◽  
Clinical Manifestations ◽  
Case Series ◽  
Diffuse Alveolar Hemorrhage ◽  
Alveolar Hemorrhage ◽  
Cobalamin Deficiency ◽  
Ground Glass ◽  
High Dose ◽  
Compound Heterozygous

Abstract Background: The clinical manifestations of combined methylmalonic acidemia (MMA) and homocysteinemia (cobalamin deficiency) vary, but typically include neurologic, developmental and hematologic abnormalities. Only a few patients had diffuse lung disease (DLD). We analyse the clinical features of cobalamin C deficiency (CblC deficiency) who developed late-onset DLD mainly diffuse alveolar hemorrhage (DAH) to strengthen an understanding of it.Results: This study describes 4 patients aged 4-years-2-months to 7-years-6-months with CblC deficiency who developed late-onset DLD. Of these, the first 3 patients presented predominantly with DAH, and the last patient with pulmonary microangiopathy confirmed by lung biopsy. All patients accompanied by pulmonary arterial hypertension (PAH), and 2 accompanied by moderate megaloblastic anemia. Diffuse ground-glass opacification and poorly defined ground-glass centrilobular nodules were seen on high-resolution computed tomography (HRCT) in 1 patient and 3 patients respectively. All patients were suspected of having idiopathic pulmonary hemosiderosis (IPH) or interstitial lung disease (ILD) at other hospitals. The last 2 patients received treatment with high dose corticosteroid before admission, but the symptoms didn’t improve. Moreover, all patients carried compound heterozygous mutations (c.80A>G, c.609G>A) and improved significantly after being treated for CblC deficiency and PAH.Conclusions: CblC deficiency should be considered in the differential diagnosis of DAH especially with PAH, and pulmonary microangiopathy be the main reason of DLD in these patients.

MEVALONATE KINASE DEFICIENCY IN AN INFANT: KEY ASPECTS OF DIAGNOSIS AND TREATMENT

2021 ◽  
Vol 100 (2) ◽  
pp. 276-283
Author(s):  
M.F. Dubko ◽  
◽  
R.K. Raupov ◽  
M.A. Kaneva ◽  
E.N. Suspitsyn ◽  
...  
Keyword(s):  
Late Onset ◽  
Interleukin 1 ◽  
Clinical Manifestations ◽  
Specific Treatment ◽  
Autosomal Recessive Inheritance ◽  
Compound Heterozygous ◽  
Mevalonate Kinase Deficiency ◽  
Mevalonate Kinase ◽  
Pathogenic Variants ◽  
Severe Type

Mevalonate kinase deficiency (MKD) is a rare autoinflammatory disease with an autosomal recessive inheritance. The severity of the disease is correlated with the residual enzyme activity. There are two types of mevalonate kinase deficiency: a less severe type called hyperimmunoglobulinemia D syndrome (HIDS) and a more severe type called mevalonic aciduria. A little more than 300 cases with MDK have been described worldwide. The rarity of this disease, and polymorphism of clinical manifestations lead to late diagnosis and late onset of specific treatment. We described the 7-month-old infant with pathogenic variants c.118C> T (p.R40W) and c.206_207del (p.S69fs) in the MVK gene in a compound heterozygous state with the successful use of an interleukin-1 blocker.

scholarly journals AB0521 COST OF ILLNESS OF ANCA-ASSOCIATED VASCULITIS IN ITALY: DATA LINKAGE ANALYSIS OF MULTIPLE CLINICAL AND ADMINISTRATIVE DATABASES IN THE PROVINCE OF UDINE, ITALY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1558.1-1558
Author(s):  
L. Quartuccio ◽  
E. Treppo ◽  
S. De Vita ◽  
F. Valent
Keyword(s):  
Health Care ◽  
Cost Of Illness ◽  
Systemic Vasculitis ◽  
Health Information System ◽  
Clinical Manifestations ◽  
Administrative Databases ◽  
Rank Test ◽  
Hospital Discharges ◽  
Severe Infections ◽  
Regional Population

Background:ANCA-associated vasculitides (AAV) are a group of systemic vasculitis carrying a high risk of hospitalization because the multiorgan involvement, the acute nature of some clinical manifestations, the chronic but very disabling course of some other manifestations and finally the risk of severe infections due to chronic glucocorticoid and immunosuppressor administration. However, data on cost of illness due to AAV are lacking.Objectives:to estimate the cost of illness in patients suffering from AAV in the province of Udine (about 500,000 inhabitants), Friuli Venezia Giulia (FVG), Italy, from year 2010 to 2018.Methods:integration of the information coming from many administrative databases were used to this end. The Regional Health Information System of FVG was used as the source of information for this retrospective cohort study. The system covers the entire regional population and includes various electronic health administrative databases that can be linked with one another on an individual basis through a unique encrypted identifier. In particular, the following databases were matched: the database of the health care beneficiaries (including demographic information and the residential history of all of the subjects living in FVG), the hospital discharge database, the database of exemptions from medical charges, the database of the laboratories. The population under study was selected based on the following inclusion criteria: patients were residents in the province of Udine and they had to carry the exemption code for AAV, including GPA, or EGPA, or MPA. This population was observed from 2010 to 2018.Results:57 patients (201 patient-years) with AAV were identified. They were ANCA-positive in 44/57 (77%). GPA, EGPA and MPA was diagnosed in 18 (31,6%), 15 (26,3%), 11 (19,3%) patients, respectively. The mean age at diagnosis was 54,5 (17,5) years. The disease itself was the main cause of hospitalization in almost half of the hospital discharges (60/126, 47,6%). Four patients died during the observation period due to vasculitis itself (1), pneumonia (2), or haematological malignancy (1). Time to the first event (death or hospitalization) was significantly higher in ANCA-negative AAV patients than in ANCA-positive AAV patients (p=0,03, Log-Rank test), ANCA-positive AAV patients having a three-times higher risk (HR 3,38 95%CI 1,13-10,08, p=0,03). Total estimated cost was € 1,215,078, corresponding to € 6,168 patient-year. Costs for ANCA-positive AAV patients were much higher than those for ANCA-negative AAV patients (€ 1,115,253 vs € 99,825, and € 7058 per person-year vs € 2,559 per person-year, respectively). GPA and MPA showed the highest costs if compared to EGPA [GPA: € 239,168 (€ 5199 per person-year) vs MPA: € 281,502 (€ 4771 per person-year) vs EGPA: € 214,287 (2329 per person-year), respectively]. Costs for hospitalization were the highest [€ 734,957 (€ 3731 per person-year) vs other costs € 480,121 (€ 2437 per person-year)].Conclusion:costs for AAV are very high, confirming the high health care burden of this illness. Management of ANCA-positive patients rather than ANCA-negative patients was burdened by the highest costs. GPA and MPA showed the highest direct costs for hospitalization, which very frequently occurred due to the vasculitis itself.Disclosure of Interests:Luca Quartuccio Consultant of: Abbvie, Bristol, Speakers bureau: Abbvie, Pfizer, Elena Treppo: None declared, Salvatore De Vita Consultant of: Roche, GSK, Speakers bureau: Roche, GSK, Novartis, Francesca Valent: None declared

scholarly journals Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families

2021 ◽  
Vol 22 (7) ◽  
pp. 3625
Author(s):  
Filomena Napolitano ◽  
Giorgia Bruno ◽  
Chiara Terracciano ◽  
Giuseppina Franzese ◽  
Nicole Piera Palomba ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Rare Variants ◽  
Clinical Symptoms ◽  
Late Onset ◽  
Respiratory Muscles ◽  
Autosomal Recessive Disorder ◽  
Compound Heterozygous ◽  
Enzyme Replacement ◽  
Whole Exome ◽  
Clinical Pictures

Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype–phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.

The Molecular Basis of Beta-Thalassemia Intermedia in Egyptian Children and its Association with the Clinical Phenotype

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Iman Ahmed Ragab ◽  
Shereen Mohamed Abd El-Ghany ◽  
Tarek Mostafa Kamal ◽  
Ghada Samir Abd El-Halim Elsayed
Keyword(s):  
Clinical Manifestations ◽  
Cross Sectional Study ◽  
Beta Thalassemia ◽  
Compound Heterozygous ◽  
Beta Globin ◽  
Thalassemia Intermedia ◽  
Cross Sectional ◽  
Pediatric Hematology ◽  
Egyptian Children ◽  
Degrees Of Severity

Abstract Background β-thalassemia syndromes involve a collection of extremely diverse phenotypes. The term β-thalassemia intermedia (β-TI) was suggested to describe patients who had clinical manifestations that are too severe to be termed minor thalassemia yet too mild to be termed major thalassemia. However, there remains substantial overlap between the three conditions. Aim of the Work To evaluate the variable clinical phenotypes among pediatric patients with βTI and to study the phenotype / genotype correlation with the encountered β-chain mutations. Patients and Methods A cross-sectional study was conducted on 37 Egyptian children and adolescents with TI following up regularly in the Pediatric Hematology clinic – Ain Shams University. Detailed Clinical evaluation and laboratory investigations were done. Reverse hybridization PCR based assay covering beta globin Mediterranean mutations onto specific biotinylated primers, was done. Results IVS 1.6 (T>C) was the most frequent mutation detected in 20 patients and 31 alleles (47.7%), followed by IVS 1.110 (G>A) detected in 7 patients and 8 alleles (12.31%), followed by IVS 1.1 (G>A) and CD27 knossos (G>T), each was detected in 6 patients and 6 alleles (9.23%). β+β+ was the most frequent genotype (54%), followed by β+β/β°β (21.6%) and β°β+ (13.5%). 60% of β°β+ patients had TDT(Transfusion dependent thalassemia), while 87.5% of β + β/β°β patients and 55% of β + β+ patients had NTDT ((Non transfusion dependent thalassemia). Conclusion Inheritance of mild β+ thalassemia mutations among Egyptian children; as IVS 1.6 (T>C) and IVS 1.110 (G>A) is the most frequent contributor to TI phenotype in either homozygous or compound heterozygous states. Patients with the same underlying genotype presented variable phenotypes with different degrees of severity.

scholarly journals Is Staphylococcus lugdunensis Significant in Clinical Samples?

2017 ◽  
Vol 55 (11) ◽  
pp. 3167-3174 ◽  
Author(s):  
Xavier Argemi ◽  
Yves Hansmann ◽  
Philippe Riegel ◽  
Gilles Prévost
Keyword(s):  
Pathogenic Bacteria ◽  
Clinical Manifestations ◽  
Clinical Samples ◽  
Opportunistic Pathogens ◽  
Coagulase Negative Staphylococci ◽  
Staphylococcus Lugdunensis ◽  
Content Type ◽  
Severe Infections ◽  
Microbiological Data

ABSTRACTThe implication of coagulase-negative staphylococci in human diseases is a major issue, particularly in hospital settings wherein these species often act as opportunistic pathogens. In addition, some coagulase-negative staphylococci such asS. lugdunensishave emerged as pathogenic bacteria, implicated in severe infections, particularly, osteoarticular infections, foreign-body-associated infections, bacteremia, and endocarditis.In vitrostudies have shown the presence of several putative virulence factors such as adhesion factors, biofilm production, and proteolytic factors that might explain clinical manifestations. Taken together, the clinical and microbiological data might change the way clinicians and microbiologists look atS. lugdunensisin clinical samples.

scholarly journals Genome editing using CRISPR-Cas9 to create the HPFH genotype in HSPCs: An approach for treating sickle cell disease and β-thalassemia

2016 ◽  
Vol 113 (38) ◽  
pp. 10661-10665 ◽  
Author(s):  
Lin Ye ◽  
Jiaming Wang ◽  
Yuting Tan ◽  
Ashley I. Beyer ◽  
Fei Xie ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Genome Editing ◽  
Sickle Cell ◽  
Globin Gene ◽  
Autologous Transplantation ◽  
Clinical Manifestations ◽  
Fetal Hemoglobin ◽  
Compound Heterozygous ◽  
Cell Disease ◽  
Hematopoietic Stem

Hereditary persistence of fetal hemoglobin (HPFH) is a condition in some individuals who have a high level of fetal hemoglobin throughout life. Individuals with compound heterozygous β-thalassemia or sickle cell disease (SCD) and HPFH have milder clinical manifestations. Using RNA-guided clustered regularly interspaced short palindromic repeats-associated Cas9 (CRISPR-Cas9) genome-editing technology, we deleted, in normal hematopoietic stem and progenitor cells (HSPCs), 13 kb of the β-globin locus to mimic the naturally occurring Sicilian HPFH mutation. The efficiency of targeting deletion reached 31% in cells with the delivery of both upstream and downstream breakpoint guide RNA (gRNA)-guided Staphylococcus aureus Cas9 nuclease (SaCas9). The erythroid colonies differentiated from HSPCs with HPFH deletion showed significantly higher γ-globin gene expression compared with the colonies without deletion. By T7 endonuclease 1 assay, we did not detect any off-target effects in the colonies with deletion. We propose that this strategy of using nonhomologous end joining (NHEJ) to modify the genome may provide an efficient approach toward the development of a safe autologous transplantation for patients with homozygous β-thalassemia and SCD.

scholarly journals Intensity of Nematode Infection in Children Aged 3 to 5 Years Living in Mukuru Kwa Njenga Slum Settlement, Nairobi, Kenya

2020 ◽  
Vol 2020 ◽  
pp. 1-7 ◽  
Author(s):  
Lynda Allan ◽  
Fiona N. Mbai ◽  
Dorcas S. Yole ◽  
Moses Owino
Keyword(s):  
Health Workers ◽  
Clinical Manifestations ◽  
Infection Intensity ◽  
Nematode Infection ◽  
Intensity Of Infection ◽  
Mean Intensity ◽  
Number Of Children ◽  
The Status ◽  
Severe Infections ◽  
Stool Samples

Background. The burden of nematode infections is high mostly in children below 5 years old, with clinical manifestations ranging from mild to painful symptoms due to severe infections that end up suppressing the immune system of the infected children. The occurrence of these infections is highest in areas of extreme poverty. This study evaluated the intensity of nematode infections and assessed the status of deworming in children aged 3 to 5 years living in Mukuru slum settlement, Nairobi County, Kenya. Methodology. A total of 172 children aged between 3 and 5 years were sampled across the 5 major villages of Mukuru Slum settlement: Kwa Njenga, Vietnum, Wapewape, Kwa Reuben, and Motomoto. Community health workers administered questionnaires on the deworming history of children. Stool samples were collected, macroscopically examined, and microscopically analysed using Kato-Katz technique to assess the intensity of infection. The intensities of nematode infections were expressed as eggs per gram (epg) of faeces. Results. The point prevalence of nematode infection among the 98 children in the 1st sampling was 25.5% with a mean infection intensity of 5424 epg, whereas among the 74 children sampled in 2nd sampling, 47.3% had nematode infection with a mean infection intensity of 12384 epg. The average nematode infection for the 172 participants was 34.9% with a mean intensity of 17808 epg. The highest number of children infected with nematodes was in the village of Wapewape where 34 participants were examined and 36.3% were infected with a mean intensity of 3216 epg. Kwa Reuben and Vietnum villages had the same prevalence values of 32.4% where 34 participants in each village had a mean intensity of 3624 epg and 4512 epg, respectively. In both samplings, more than 80% of children had been dewormed more than 6 months prior to the study. Ascaris lumbricoides was the only species of intestinal nematodes identified to be present in the stool samples of children in this study, whereas Trichuris trichiura and hookworm infections were found to be absent. The intensity of infection was not dependent on age or gender.

Late-onset versus early-onset systemic lupus: characteristics and outcome in a national multicentre register (RELESSER)

Rheumatology ◽  
2020 ◽  
Author(s):  
Anne Riveros Frutos ◽  
Susana Holgado ◽  
Arantza Sanvisens Bergé ◽  
Irma Casas ◽  
Alejandro Olivé ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Early Onset ◽  
Clinical Course ◽  
Late Onset ◽  
Immunosuppressive Agents ◽  
Diagnostic Delay ◽  
Clinical Manifestations ◽  
Diagnostic Errors ◽  
Systemic Lupus ◽  
Female Ratio

Abstract Objective The aim of the present study was to describe the demographic, clinical and immunological characteristics of patients with late-onset (≥50 years) SLE vs patients with early-onset SLE (<50 years). Methods We performed a cross-sectional retrospective study of 3619 patients from the RELESSER database (National Register of Patients with Systemic Lupus Erythematosus of the Spanish Society of Rheumatology). Results A total of 565 patients (15.6%) were classified as late-onset SLE and 3054 (84.4%) as early-onset SLE. The male-to-female ratio was 5:1. Mean (s.d.) age at diagnosis in the late-onset group was 57.4 (10.4) years. At diagnosis, patients with late-onset SLE had more comorbid conditions than patients with early-onset SLE; the most frequent was cardiovascular disease (P <0.005). Furthermore, diagnostic delay was longer in patients with late-onset SLE [45.3 (3.1) vs 28.1 (1.0); P <0.001]. Almost all patients with late-onset SLE (98.7%) were Caucasian. Compared with early-onset SLE and after adjustment for time since diagnosis, patients with late-onset SLE more frequently had serositis, major depression, thrombotic events, cardiac involvement and positive lupus anticoagulant values. They were also less frequently prescribed immunosuppressive agents. Mortality was greater in late-onset SLE (14.3% vs 4.7%; P <0.001). Conclusion Late-onset SLE is insidious, with unusual clinical manifestations that can lead to diagnostic errors. Clinical course is generally indolent. Compared with early-onset disease, activity is generally reduced and immunosuppressants are less commonly used. Long-term prospective studies are necessary to determine whether the causes of death are associated with clinical course or with age-associated comorbidities in this population.

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