Papular Purpuric Glove and Socks Syndrome with Evolution into Pemphigus Vulgaris.

Ann Acad Med Singapore. 2018 Oct;47(10):429-430

Authors: Phuan CZ, Tan LS, Tey HL

Abstract

PMID: 30460971 [PubMed - indexed for MEDLINE]

A gene-centric strategy for identifying disease-causing rare variants in dilated cardiomyopathy.

Genet Med. 2019 01;21(1):133-143

Authors: Horvat C, Johnson R, Lam L, Munro J, Mazzarotto F, Roberts AM, Herman DS, Parfenov M, Haghighi A, McDonough B, DePalma SR, Keogh AM, Macdonald PS, Hayward CS, Roberts A, Barton PJR, Felkin LE, Giannoulatou E, Cook SA, Seidman JG, Seidman CE, Fatkin D

Abstract
PURPOSE: We evaluated strategies for identifying disease-causing variants in genetic testing for dilated cardiomyopathy (DCM).
METHODS: Cardiomyopathy gene panel testing was performed in 532 DCM patients and 527 healthy control subjects. Rare variants in 41 genes were stratified using variant-level and gene-level characteristics.
RESULTS: A majority of DCM cases and controls carried rare protein-altering cardiomyopathy gene variants. Variant-level characteristics alone had limited discriminative value. Differentiation between groups was substantially improved by addition of gene-level information that incorporated ranking of genes based on literature evidence for disease association. The odds of DCM were increased to nearly 9-fold for truncating variants or high-impact missense variants in the subset of 14 genes that had the strongest biological links to DCM (P <0.0001). For some of these genes, DCM-associated variants appeared to be clustered in key protein functional domains. Multiple rare variants were present in many family probands, however, there was generally only one "driver" pathogenic variant that cosegregated with disease.
CONCLUSION: Rare variants in cardiomyopathy genes can be effectively stratified by combining variant-level and gene-level information. Prioritization of genes based on their a priori likelihood of disease causation is a key factor in identifying clinically actionable variants in cardiac genetic testing.

PMID: 29892087 [PubMed - indexed for MEDLINE]

Does genomic sequencing early in the diagnostic trajectory make a difference? A follow-up study of clinical outcomes and cost-effectiveness.

Genet Med. 2019 01;21(1):173-180

Authors: Stark Z, Schofield D, Martyn M, Rynehart L, Shrestha R, Alam K, Lunke S, Tan TY, Gaff CL, White SM

Abstract
PURPOSE: To systematically investigate the longer-term clinical and health economic impacts of genomic sequencing for rare-disease diagnoses.
METHODS: We collected information on continuing diagnostic investigation, changes in management, cascade testing, and parental reproductive outcomes in 80 infants who underwent singleton whole-exome sequencing (WES).
RESULTS: The median duration of follow-up following result disclosure was 473 days. Changes in clinical management due to diagnostic WES results led to a cost saving of AU$1,578 per quality-adjusted life year gained, without increased hospital service use. Uninformative WES results contributed to the diagnosis of non-Mendelian conditions in seven infants. Further usual diagnostic investigations in those with ongoing suspicion of a genetic condition yielded no new diagnoses, while WES data reanalysis yielded four. Reanalysis at 18 months was more cost-effective than every 6 months. The parents of diagnosed children had eight more ongoing pregnancies than those without a diagnosis. Taking the costs and benefits of cascade testing and reproductive service use into account, there was an additional cost of AU$8,118 per quality-adjusted life year gained due to genomic sequencing.
CONCLUSION: These data strengthen the case for the early use of genomic testing in the diagnostic trajectory, and can guide laboratory policy on periodic WES data reanalysis.

PMID: 29765138 [PubMed - indexed for MEDLINE]

8 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 2019/03/12

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.

8 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 2019/03/12

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.

Phenotype-loci associations in networks of patients with rare disorders: application to assist in the diagnosis of novel clinical cases.

Eur J Hum Genet. 2018 10;26(10):1451-1461

Authors: Bueno A, Rodríguez-López R, Reyes-Palomares A, Rojano E, Corpas M, Nevado J, Lapunzina P, Sánchez-Jiménez F, Ranea JAG

Abstract
Copy number variations (CNVs) are genomic structural variations (deletions, duplications, or translocations) that represent the 4.8-9.5% of human genome variation in healthy individuals. In some cases, CNVs can also lead to disease, being the etiology of many known rare genetic/genomic disorders. Despite the last advances in genomic sequencing and diagnosis, the pathological effects of many rare genetic variations remain unresolved, largely due to the low number of patients available for these cases, making it difficult to identify consistent patterns of genotype-phenotype relationships. We aimed to improve the identification of statistically consistent genotype-phenotype relationships by integrating all the genetic and clinical data of thousands of patients with rare genomic disorders (obtained from the DECIPHER database) into a phenotype-patient-genotype tripartite network. Then we assessed how our network approach could help in the characterization and diagnosis of novel cases in clinical genetics. The systematic approach implemented in this work is able to better define the relationships between phenotypes and specific loci, by exploiting large-scale association networks of phenotypes and genotypes in thousands of rare disease patients. The application of the described methodology facilitated the diagnosis of novel clinical cases, ranking phenotypes by locus specificity and reporting putative new clinical features that may suggest additional clinical follow-ups. In this work, the proof of concept developed over a set of novel clinical cases demonstrates that this network-based methodology might help improve the precision of patient clinical records and the characterization of rare syndromes.

PMID: 29946186 [PubMed - indexed for MEDLINE]

Right ventricular pseudoaneurysm.

Eur Heart J Cardiovasc Imaging. 2018 07 01;19(7):823

Authors: Sakaguchi T, Akagi S, Totsugawa T, Tamura K, Hiraoka A

PMID: 29481582 [PubMed - indexed for MEDLINE]

Genetic convergence of rare lymphomas.

Curr Opin Hematol. 2018 07;25(4):307-314

Authors: Shingleton JR, Dave SS

Abstract
PURPOSE OF REVIEW: We review the genetic foundations of different rare lymphomas to examine their shared origins. These data indicate the potential application of genomics to improve the diagnosis and treatment of these rare diseases.
RECENT FINDINGS: Next generation sequencing technologies have provided an important window into the genetic underpinnings of lymphomas. A growing body of evidence indicates that although some genetic alterations are specific to certain diseases, others are shared across different lymphomas. Many such genetic events have already demonstrated clinical utility, such as BRAF V600E that confers sensitivity to vemurafenib in patients with hairy cell leukemia.
SUMMARY: The rareness of many lymphoma subtypes makes the conduct of clinical trials and recruitment of significant numbers of patients impractical. However, a knowledge of the shared genetic origins of these rare lymphomas has the potential to inform 'basket' clinical trials in which multiple lymphoma subtypes are included. These trials would include patients based on the presence of alterations in targetable driver genes. Such approaches would be greatly strengthened by a systematic assessment of significant patient numbers from each subtype using next generation sequencing.

PMID: 29702524 [PubMed - indexed for MEDLINE]

What Does the New Ontario Pharmacare Plan offer Children and Young Adults with Rare Disorders?

J Popul Ther Clin Pharmacol. 2017 12 01;24(3):90-98

Authors: Rawson N

Abstract
A publicly-funded pharmacare program (OHIP+) was announced in the 2017 Ontario budget for all children and young adults that will begin in January 2018 and cover drugs in the Ontario Public Drug Programs (OPDP) formulary. In this commentary, drugs indicated for rare disorders commonly occurring in childhood that were reviewed by the Common Drug Review (CDR) between 2004 and 2016 are examined to assess the Ontario reimbursement situation. OPDP reimburse few of these drugs and only about half of those covered are accessible with consistency and without onerous conditions. Providing reimbursement for rare disorder drugs that received a positive CDR recommendation would likely cost less than a quarter of OHIP+'s projected cost. Children who will benefit most from OHIP+ are those with common conditions whose parents do not presently have access to provincial or private insurance. Children with rare disorders deserve accessible provincial financial support for potentially life-transforming drugs.

PMID: 29432671 [PubMed - indexed for MEDLINE]

Fibrolamellar carcinoma in the Carney complex: PRKAR1A loss instead of the classic DNAJB1-PRKACA fusion.

Hepatology. 2018 10;68(4):1441-1447

Authors: Graham RP, Lackner C, Terracciano L, González-Cantú Y, Maleszewski JJ, Greipp PT, Simon SM, Torbenson MS

Abstract
Fibrolamellar carcinomas are characterized by activation of protein kinase A, a kinase composed of catalytic and regulatory subunits. PRKACA encodes a catalytic subunit of protein kinase A, and almost all fibrolamellar carcinomas have a heterozygous 400-kb deletion that leads to the fusion of DNAJB1 and PRKACA. The resulting DNAJB1-PRKACA fusion transcript is believed to activate protein kinase A by dysregulation of the catalytic portion of the protein. In contrast, PRKAR1A encodes one of the regulatory subunits of protein kinase A. We hypothesized that loss of function of this regulatory unit could also lead to protein kinase A activation and thus to fibrolamellar carcinoma. Because PRKAR1A mutations underlie the Carney complex, we searched for liver tumors in individuals with the Carney complex. We identified 3 individuals with fibrolamellar carcinomas and a personal history of the Carney complex. All three tumors displayed the typical morphology of fibrolamellar carcinoma and were positive for arginase, cytokeratin 7, and cluster of differentiation 68. Fluorescence in situ hybridization was negative for PRKACA rearrangements. However, PRKAR1A sequencing identified pathogenic mutations in two of two cases with successful sequencing. In addition, all three cases were negative for PRKAR1A protein expression, consistent with inactivation of this key regulatory unit of protein kinase A. We also identified one additional fibrolamellar carcinoma in an individual without a documented history of the Carney complex who was negative for PRKACA rearrangements but had loss of PRKAR1A protein expression as well as PRKAR1A mutations.
CONCLUSION: Fibrolamellar carcinoma can be part of the Carney complex; in this setting, fibrolamellar carcinomas have inactivating PRKAR1A mutations instead of the DNAJB1-PRKACA fusion gene found in sporadic fibrolamellar carcinomas, providing an alternate means for activation of protein kinase A. (Hepatology 2017).

PMID: 29222914 [PubMed - indexed for MEDLINE]

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 2019/03/07

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.

The current landscape of European registries for rare endocrine conditions.

Eur J Endocrinol. 2019 Jan 01;180(1):89-98

Authors: Ali SR, Bryce J, Cools M, Korbonits M, Beun JG, Taruscio D, Danne T, Dattani M, Dekkers OM, Linglart A, Netchine I, Nordenstrom A, Patocs A, Persani L, Reisch N, Smyth A, Sumnik Z, Visser WE, Hiort O, Pereira AM, Ahmed SF

Abstract
Objective To identify cross-border international registries for rare endocrine conditions that are led from Europe and to understand the extent of engagement with these registries within a network of reference centres (RCs) for rare endocrine conditions. Methods Database search of international registries and a survey of RCs in the European Reference Network for rare endocrine conditions (Endo-ERN) with an overall response rate of 82%. Results Of the 42 conditions with orphacodes currently covered within Endo-ERN, international registries exist for 32 (76%). Of 27 registries identified in the Orphanet and RD-Connect databases, Endo-ERN RCs were aware of 11 (41%). Of 21 registries identified by the RC, RD-Connect and Orphanet did not have a record of 10 (48%). Of the 29 glucose RCs, the awareness and participation rate in an international registry was highest for rare diabetes at 75 and 56% respectively. Of the 37 sex development RCs, the corresponding rates were highest for disorders of sex development at 70 and 52%. Of the 33 adrenal RCs, the rates were highest for adrenocortical tumours at 68 and 43%. Of the 43 pituitary RCs, the rates were highest for pituitary adenomas at 43 and 29%. Of the 31 genetic tumour RCs, the rates were highest for MEN1 at 26 and 9%. For the remaining conditions, awareness and participation in registries was less than 25%. Conclusion Although there is a need to develop new registries for rare endocrine conditions, there is a more immediate need to improve the awareness and participation in existing registries.

PMID: 30407922 [PubMed - indexed for MEDLINE]

Disease and economic burden for rare diseases in Taiwan: A longitudinal study using Taiwan's National Health Insurance Research Database.

PLoS One. 2018;13(9):e0204206

Authors: Hsu JC, Wu HC, Feng WC, Chou CH, Lai EC, Lu CY

Abstract
BACKGROUND: High-cost orphan drugs are becoming increasingly available to treat rare diseases that affect a relatively small population. Little attention has been given to the prevalence of rare diseases and their health-related economic burden in Taiwan.
OBJECTIVES: This study examined the national trends in the prevalence of rare diseases and their health-related economic burden (including medication costs) in Taiwan.
METHODS: Rare disease-related claims data from 2003-2014 (12 years) from the National Health Insurance Research Database were used in this study. We used a time series analysis to assess trends in the yearly rates of treated patients with rare diseases, overall healthcare use, and expenditures, including drugs.
RESULTS: During the 12-year study period, the estimated prevalence of rare diseases increased from 10.57 to 33.21 per 100,000 population, an average rate of a 19.46% increase per year. Total health expenditures for treatment of rare diseases increased from US$18.65 million to US$137.44 million between 2003 and 2014, accounting for 0.68% of the total national health expenditures in 2014. Drug expenditures for treatment of rare diseases increased from US$13.24 million to US$121.98 million between 2003 and 2014, which accounted for 71.00% and 88.75% of the health expenditures for patients with rare diseases in 2003 and 2014, respectively. In 2014, we found a 20.43-fold difference in average health expenditures and a 69.46-fold difference in average drug expenditures between patients with rare diseases and the overall population.
CONCLUSIONS: The prevalence of rare diseases and the related economic burden have grown substantially in Taiwan over the past 12 years, and these trends are likely to continue. Drug expenditures accounted for almost 90% of health expenditures for rare diseases. Further analyses are underway to examine the economic burden of individual rare diseases.

PMID: 30240449 [PubMed - indexed for MEDLINE]

7 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 2019/03/05

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.

The Therapeutic Challenge of Rare Diseases.

Mayo Clin Proc. 2018 05;93(5):560-562

Authors: Rooke T

PMID: 29643000 [PubMed - indexed for MEDLINE]

Vascular Complications After Chin Augmentation Using Hyaluronic Acid.

Aesthetic Plast Surg. 2018 Apr;42(2):553-559

Authors: Wang Q, Zhao Y, Li H, Li P, Wang J

Abstract
Vascular complications after hyaluronic acid (HA) filling of the chin have rarely been reported. In this report, two cases of vascular occlusion after HA augmentation of the mentum are presented. The first case involved local skin necrosis that resulted from a massive microcirculatory embolism and/or external compression of the chin skin microvasculature. The second case involved vascular compromise in the tongue that resulted from HA injection in the chin. The diagnosis was established on the basis of interventional angiography findings. Concerning the pathogenesis, we hypothesized that the filler embolus flowed into the branches of the deep lingual artery through the rich vascular anastomoses among the submental, sublingual, and deep lingual arteries, after being accidentally injected into the submental artery (or its branches). Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

PMID: 29260270 [PubMed - indexed for MEDLINE]

Indolent Rib Osteomyelitis Following Breast Implant Reconstruction: An Unusual Case and Review of the Literature.

Aesthetic Plast Surg. 2018 Apr;42(2):447-450

Authors: Watson L, Dunn D, Fraser-Kirk G

Abstract
Rib osteomyelitis is an infrequently occurring but important complication of breast implant surgery. Although prosthetic or surgical site infection (SSI) and rib osteomyelitis as separate entities are well described in the literature, only five cases of rib or sternal osteomyelitis related to implant placement have been reported globally. Historically patients who experience this complication have not demonstrated an identifiable prevalence of the traditional risk factors associated with SSI or rib osteomyelitis. This report describes the sequence of clinical manifestations of an unusual case of breast implants complicated by rib osteomyelitis. A 56-year-old female underwent mastectomy and insertion of tissue expanders for bilateral invasive ductal carcinoma following which the tissue expanders became infected in the early postoperative period and were subsequently removed. The patient underwent successful expander insertion and subsequent implant exchange surgery several years later and enjoyed an uncomplicated recovery from this. Following nipple reconstruction more than 12 months after successful implant placement, she presented with Staphylococcus epidermidis bacteremia and a left-sided clinical peri-implant infection. Upon removal of her implant, an intraoperative discovery of rib necrosis/osteomyelitis was made for which she was treated. To provide context, the literature was reviewed for other reported cases of rib osteomyelitis following breast implant surgery. This patient, in combination with others reported in the literature, emphasises the diagnostic difficulties posed by this condition as a result of its low incidence and variable or absent clinical features.
LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

PMID: 29026955 [PubMed - indexed for MEDLINE]

8 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 2019/03/01

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.

The difficulties and importance of research in rare genetic diseases.

Muscle Nerve. 2018 04;57(4):520-521

Authors: Hunter M, Johnson NE

PMID: 29266294 [PubMed - indexed for MEDLINE]

Transient antenatal Bartter's Syndrome and X-linked polyhydramnios: insights from the genetics of a rare condition.

Kidney Int. 2016 10;90(4):721-3

Authors: Quigley R, Saland JM

Abstract
The discovery that mutations in MAGED2 cause a rare and transient form of antenatal Bartter's Syndrome may have implications beyond the very small number of affected families. Understanding the mechanism by which this severe form of Bartter's Syndrome resolves after birth could also provide new insights into the regulation of tubular transport and the response to tissue hypoxia.

PMID: 27633862 [PubMed - indexed for MEDLINE]