Single giant mediastinal rhabdomyoma as a sole manifestation of TSC in foetus.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017 Sep;161(3):326-329

Authors: Godava M, Filipova H, Dubrava L, Vrtel R, Michalkova K, Janikova M, Bakaj-Zbrozkova L, Navratil J

Abstract
BACKGROUND: Presence of multiple cardiac rhabdomyomas is one of the major features of Tuberous sclerosis (TSC), but isolated progressing single giant rhabdomyoma is very rare and not typical of TSC.
CASE REPORT: This report presents family without obvious history of TSC with occurrence of giant mediastinal rhabdomyoma affecting the haemodynamics in male foetus, without other TSC symptoms. Girl from the next gravidity had prenatally detected multiple rhabdomyomas and small subcortical tuber of brain detected after birth. DNA analysis found novel c.4861A>T TSC2 variant and large deletion in TSC2 in tumour tissue from male foetus. The novel TSC2 variant was also present in the girl and her healthy father, in silico analysis suggested its functional effect on TSC2. Brain MRI of the father detected mild TSC specific abnormality.
CONCLUSION: We suggest the novel TSC2 mutation is a cause of mild TSC in this family and has reduced expression. The clinical and molecular findings in this family also emphasize that TSC diagnosis should be also evaluated in case of single giant foetal cardiac rhabdomyoma.

PMID: 28659645 [PubMed - indexed for MEDLINE]

Triple jeopardy for people with albinism.

Pigment Cell Melanoma Res. 2016 09;29(5):487

Authors: Arnheiter H, Long G, Aplin A, Harris J, Kelsh R

PMID: 27615283 [PubMed - indexed for MEDLINE]

Expanding the phenotypic spectrum associated with OPHN1 variants.

Eur J Med Genet. 2018 Jun 27;:

Authors: Schwartz TS, Wojcik MH, Pelletier RC, Edward HL, Picker JD, Holm IA, Towne MC, Beggs AH, Agrawal PB

Abstract
Genomic sequencing has allowed for the characterization of new gene-to-disease relationships, as well as the identification of variants in established disease genes in patients who do not fit the classically-described phenotype. This is especially true in rare syndromes where the clinical spectrum is not fully known. After a lengthy and costly diagnostic odyssey, patients with atypical presentations may be left with many questions even after a genetic diagnosis is identified. We present a 22-year old male with hypotonia, developmental delay, seizure disorder, and dysmorphic facial features who enrolled in our rare disease research center at 18 years of age, where exome sequencing revealed a novel, likely pathogenic variant in the OPHN1 gene. Through efforts by the study team and collaborations with the larger genetics community, contacts with other families with OPHN1 variants were eventually made, and outreach by these families expanded the patient network. This partnership between families and researchers facilitated the gathering of phenotypic information, allowing for comparison of clinical presentations among three new patients and those previously reported in the literature. These comparisons found previously unreported commonalities between the newly identified patients, such as the presence of otitis media and the lack of genitourinary abnormalities (i.e. hypoplastic scrotum, microphallus, cryptorchidism), which had been noted to be classic features of patients with OPHN1 variants. As genomic sequencing becomes more common, connecting patients with novel variants in the same gene will facilitate phenotypic analysis and continue to refine the clinical spectrum associated with that gene.

PMID: 29960046 [PubMed - as supplied by publisher]

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/06/30

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/06/30

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Rare cause of colonic intussusception in an adult.

BMJ Case Rep. 2017 Sep 15;2017:

Authors: Nissen A, Yi F

Abstract
Colonic intussusception is an uncommon phenomenon in adults. Advanced imaging has facilitated the increase in awareness of this rare disease. When present, the lead point is most often secondary to a malignancy with primary adenocarcinoma being the most frequent cause. Current surgical management involves oncologic resections for this reason. This is a report of the third ever-reported case of colonic intussusception secondary to an angiolipoma and the first in the western hemisphere. We also demonstrate that these masses are amenable to minimally invasive resection for definitive management.

PMID: 28918406 [PubMed - indexed for MEDLINE]

Rare case of primary leiomyosarcoma of sigmoid mesocolon.

BMJ Case Rep. 2017 Sep 15;2017:

Authors: Ilias AS, Yaacob H, Wan Zain WZ, Zakaria AD

Abstract
We experienced a rare case of primary leiomyosarcoma of sigmoid mesentery. A 45-year-old woman was presented to us with left iliac fossa mass and discomfort for 4-month duration. CT scan of abdomen and pelvis revealed a huge mass 14 cm×14 cm×16 cm occupying left iliac fossa mimicked having a large left ovarian carcinoma. She was subsequently planned for elective total abdominal hysterectomy and bilateral salpingo-oophorectomy by gynaecology team. During laparotomy, a huge mass was revealed arising from sigmoid mesentery invaded to the left lower ureter. Curative resection was done and pathological findings show the tumour being leiomyosarcoma with immunohistochemistry tests on caldesmon, desmin, smooth muscle actin and CD34 reagent all positive. Clinicopathological and literature review of this rare primary leiomyosarcoma of mesocolon was discussed in our case presentation.

PMID: 28918402 [PubMed - indexed for MEDLINE]

Cranial fasciitis of childhood (CFC): an unusual clinical case of a rare disease.

BMJ Case Rep. 2017 Sep 13;2017:

Authors: Zavras N, Poddighe D

Abstract
Cranial fasciitis of childhood (CFC) is a very uncommon tumour of the scalp, which is almost exclusively observed in the first years of life. It is a benign proliferation of fibroblasts, but its rapid growth rate may resemble a malignant disease. This disease may be suspected from clinical and radiological features, but a definitive diagnosis may be achieved only by pathological examination. We report a case whose onset was in late childhood and whose clinical and radiological characteristics were atypical.

PMID: 28903973 [PubMed - indexed for MEDLINE]

A rare presentation of type II myocardial infarction mimicking Takotsubo cardiomyopathy.

Hellenic J Cardiol. 2017 May - Jun;58(3):243-244

Authors: Tzanis G, Bonou M, Barbetseas J

PMID: 27965177 [PubMed - indexed for MEDLINE]

Recurrence of coronary arteriovenous fistulae in a rare case of bilateral right coronary and circumflex artery arteriovenous fistulae to the pulmonary artery.

Hellenic J Cardiol. 2017 May - Jun;58(3):226-227

Authors: Gasparovic I, Artemiou P, Hudec V, Hulman M

PMID: 27663960 [PubMed - indexed for MEDLINE]

A Rare Pathology of Difficult Laparoscopic Cholecystectomy: Xanthogranulomatous Cholecystitis.

J Coll Physicians Surg Pak. 2018 Apr;28(4):330-331

Authors: Milkhu CS, Jarral F, Raw D, Maliyakkal A, Fadra A, Shiwani MH

Abstract
Xanthogranulomatous cholecystitis (XGC) is a rare inflammatory condition of the gallbladder (GB). Preoperatively, it is a diagnostic challenge. One thousand and seventy nine laparoscopic cholecystectomy (LC) patients from September 2012 to June 2015 were retrospectively reviewed. Fourteen patients were identified with XGC. An analysis was carried out on this group of patients looking at postoperative pathology results, preoperative radiology, operative findings and outcome. The overall frequency of XGC was 1.3%. A thick walled GB was found in 11 patients on preoperative imaging. Retrospectively suggestive feature thick gallbladder walls with low attenuation mural nodules. No suspicion of cancer was demonstrated in the final histology or preoperatively. Five cases (36%) perforated intraoperatively. Although all were surgically challenging, no conversions to open were performed. The perforation risk could be higher. A difficult cholecystectomy should alert a surgeon to consider XGC as a diagnosis. Contrary to the popular belief, XGC was found to be difficult to differentiate from infection rather than malignancy.

PMID: 29615182 [PubMed - indexed for MEDLINE]

A review of international coverage and pricing strategies for personalized medicine and orphan drugs.

Health Policy. 2017 Dec;121(12):1240-1248

Authors: Degtiar I

Abstract
BACKGROUND: Personalized medicine and orphan drugs share many characteristics-both target small patient populations, have uncertainties regarding efficacy and safety at payer submission, and frequently have high prices. Given personalized medicine's rising importance, this review summarizes international coverage and pricing strategies for personalized medicine and orphan drugs as well as their impact on therapy development incentives, payer budgets, and therapy access and utilization.
METHODS: PubMed, Health Policy Reference Center, EconLit, Google Scholar, and references were searched through February 2017 for articles presenting primary data.
RESULTS: Sixty-nine articles summarizing 42 countries' strategies were included. Therapy evaluation criteria varied between countries, as did patient cost-share. Payers primarily valued clinical effectiveness; cost was only considered by some. These differences result in inequities in orphan drug access, particularly in smaller and lower-income countries. The uncertain reimbursement process hinders diagnostic testing. Payer surveys identified lack of comparative effectiveness evidence as a chief complaint, while manufacturers sought more clarity on payer evidence requirements. Despite lack of strong evidence, orphan drugs largely receive positive coverage decisions, while personalized medicine diagnostics do not.
CONCLUSIONS: As more personalized medicine and orphan drugs enter the market, registries can provide better quality evidence on their efficacy and safety. Payers need systematic assessment strategies that are communicated with more transparency. Further studies are necessary to compare the implications of different payer approaches.

PMID: 29033060 [PubMed - indexed for MEDLINE]

An open source microcontroller based flume for evaluating swimming performance of larval, juvenile, and adult zebrafish.

PLoS One. 2018;13(6):e0199712

Authors: Widrick JJ, Gibbs DE, Sanchez B, Gupta VA, Pakula A, Lawrence C, Beggs AH, Kunkel LM

Abstract
Zebrafish are a preferred vertebrate model for delineating genotype-phenotype relationships. One of the most studied features of zebrafish is their exceptional swimming ability. By 7 days postfertilization (dpf), zebrafish spend over two-thirds of their time engaged in spontaneous swimming activity and several months later they are capable of attaining some of the fastest swimming velocities relative to body length ever recorded in the laboratory. However, laboratory-assembled flumes capable of achieving the slow flow velocities characteristics of larvae as well as the relatively fast maximal velocities of adults have not been described in sufficient detail to allow easy replication. Here we describe an easily assembled, open-source zebrafish-scaled flume for assessing swimming performance. The flume uses two independent spherical-impeller pumps modulated by a microcontroller to achieve flow velocities ranging from 1 to 70 cm s-1. The microcontroller also monitors water temperature and flow velocity and sends these data to a personal computer for real-time display and storage. Incremental protocols for assessing maximal swimming speed (Umax) were developed, stored in custom software, and then uploaded to the microcontroller in order to assess performance of larval (14, 21, 28 dpf), juvenile (35, 42 dpf), and adult (8, 22 month) zebrafish. The flume had sufficient range and sensitivity to detect developmental changes in Umax of larvae and juveniles, an 18-24% faster Umax of adult males vs. females, and a 14-20% age-related reduction in Umax for the oldest zebrafish. Detailed information is provided to assemble and operate this low-cost, versatile, and reliable tool for assessing zebrafish swimming performance.

PMID: 29944715 [PubMed - in process]

Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population.

PLoS Genet. 2018 05;14(5):e1007329

Authors: Rivas MA, Avila BE, Koskela J, Huang H, Stevens C, Pirinen M, Haritunians T, Neale BM, Kurki M, Ganna A, Graham D, Glaser B, Peter I, Atzmon G, Barzilai N, Levine AP, Schiff E, Pontikos N, Weisburd B, Lek M, Karczewski KJ, Bloom J, Minikel EV, Petersen BS, Beaugerie L, Seksik P, Cosnes J, Schreiber S, Bokemeyer B, Bethge J, International IBD Genetics Consortium, NIDDK IBD Genetics Consortium, T2D-GENES Consortium, Heap G, Ahmad T, Plagnol V, Segal AW, Targan S, Turner D, Saavalainen P, Farkkila M, Kontula K, Palotie A, Brant SR, Duerr RH, Silverberg MS, Rioux JD, Weersma RK, Franke A, Jostins L, Anderson CA, Barrett JC, MacArthur DG, Jalas C, Sokol H, Xavier RJ, Pulver A, Cho JH, McGovern DPB, Daly MJ

Abstract
As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim (hosted in part at https://ibd.broadinstitute.org, also available in gnomAD at http://gnomad.broadinstitute.org). We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 148 AJ enriched protein-altering alleles that overlap with "pathogenic" ClinVar alleles (table available at https://github.com/macarthur-lab/clinvar/blob/master/output/clinvar.tsv), including those that account for 10-100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases, especially recessive conditions, including Gaucher disease (GBA, p.Asn409Ser, 8-fold enrichment); Canavan disease (ASPA, p.Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (HEXA, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohn's disease, a common disease with an estimated two to four-fold excess prevalence in AJ. We specifically attempt to evaluate whether strong acting rare alleles, particularly protein-truncating or otherwise large effect-size alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohn's disease in AJ, and find that ten rare genetic risk factors in NOD2 and LRRK2 are enriched in AJ (p < 0.005), including several novel contributing alleles, show evidence of association to CD. Independently, we find that genomewide common variant risk defined by GWAS shows a strong difference between AJ and non-AJ European control population samples (0.97 s.d. higher, p<10-16). Taken together, the results suggest coordinated selection in AJ population for higher CD risk alleles in general. The results and approach illustrate the value of exome sequencing data in case-control studies along with reference data sets like ExAC (sites VCF available via FTP at ftp.broadinstitute.org/pub/ExAC_release/release0.3/) to pinpoint genetic variation that contributes to variable disease predisposition across populations.

PMID: 29795570 [PubMed - indexed for MEDLINE]

Common α-globin variants modify hematologic and other clinical phenotypes in sickle cell trait and disease.

PLoS Genet. 2018 03;14(3):e1007293

Authors: Raffield LM, Ulirsch JC, Naik RP, Lessard S, Handsaker RE, Jain D, Kang HM, Pankratz N, Auer PL, Bao EL, Smith JD, Lange LA, Lange EM, Li Y, Thornton TA, Young BA, Abecasis GR, Laurie CC, Nickerson DA, McCarroll SA, Correa A, Wilson JG, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Hematology & Hemostasis, Diabetes, and Structural Variation TOPMed Working Groups, Lettre G, Sankaran VG, Reiner AP

Abstract
Co-inheritance of α-thalassemia has a significant protective effect on the severity of complications of sickle cell disease (SCD), including stroke. However, little information exists on the association and interactions for the common African ancestral α-thalassemia mutation (-α3.7 deletion) and β-globin traits (HbS trait [SCT] and HbC trait) on important clinical phenotypes such as red blood cell parameters, anemia, and chronic kidney disease (CKD). In a community-based cohort of 2,916 African Americans from the Jackson Heart Study, we confirmed the expected associations between SCT, HbC trait, and the -α3.7 deletion with lower mean corpuscular volume/mean corpuscular hemoglobin and higher red blood cell count and red cell distribution width. In addition to the recently recognized association of SCT with lower estimated glomerular filtration rate and glycated hemoglobin (HbA1c), we observed a novel association of the -α3.7 deletion with higher HbA1c levels. Co-inheritance of each additional copy of the -α3.7 deletion significantly lowered the risk of anemia and chronic kidney disease among individuals with SCT (P-interaction = 0.031 and 0.019, respectively). Furthermore, co-inheritance of a novel α-globin regulatory variant was associated with normalization of red cell parameters in individuals with the -α3.7 deletion and significantly negated the protective effect of α-thalassemia on stroke in 1,139 patients with sickle cell anemia from the Cooperative Study of Sickle Cell Disease (CSSCD) (P-interaction = 0.0049). Functional assays determined that rs11865131, located in the major alpha-globin enhancer MCS-R2, was the most likely causal variant. These findings suggest that common α- and β-globin variants interact to influence hematologic and clinical phenotypes in African Americans, with potential implications for risk-stratification and counseling of individuals with SCD and SCT.

PMID: 29590102 [PubMed - indexed for MEDLINE]

Pharmacology and drug development in rare diseases: the attractiveness and expertise of the French medical pharmacology.

Fundam Clin Pharmacol. 2017 Dec;31(6):685-694

Authors: Micallef J, Boutouyrie P, Blin O

Abstract
Developing drugs for rare disease can be challenging due to specific rare disease characteristics. The French Medical Pharmacology is structured and positioned to play a major role in orphan drug research and development due to the required expertise concentrated into pharmacology departments, exclusively implemented within the French university hospitals, public hospitals that are linked to a medical school (and often a pharmacy school) with numerous INSERM or CNRS labelled research units. In addition, these structures allow a close collaboration between researchers, academic institutions and biotech start-up (most of them being spin-off of the academic structures). Also, within university hospitals are located the clinical investigation centres, linking to the F-CRIN network and also to Inserm and hospitals, that enable care staff and researchers to be associated and clinical research protocols to be carried out on site, in full respect with ethic and regulatory aspects. As a consequence, this intra and multidisciplinary expertise offers all resource to elaborate a tailored approach for orphan drug development, in new entities as well as in repositioning. For preclinical development: drug screening, candidate selection (taking into account PK, metabolism, variability and potential toxicity) and preclinical models (iPS, animal models) that could allow a better translation to human research. For clinical development, we will mention here dose determination, safety evaluation and Orphan Drug Designation and Protocol Assistance preparation and submission. For post marketing evaluation and surveys, the pharmacovigilance, addictovigilance and pharmacoepidemiology expertise, combined with access to large databases allow a better approach to orphan drug use and safety. As outlined through two success stories (Charcot Marie Tooth, vascular Ehlers-Danlos syndrome), the added value of French Medical Pharmacology structures and expertise has been evidenced in the know-how, multidimensional and multidisciplinary approaches, allowing the development of numerous drugs that have been granted with Orphan Drug Designation and later Market Approval. Even if specific and possibly even more, the field of orphan drugs requires the respect of highest standards of safety and quality. French Medical Pharmacology intends to continue on this way and constantly improve his involvement in this field, committed to a single objective: answer the unmet medical need of patients with rare diseases.

PMID: 28779530 [PubMed - indexed for MEDLINE]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/06/26

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/06/22

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

23 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/06/21

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

23 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/06/21

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.