The role of registries in rare genetic lipid disorders: Review and introduction of the first global registry in lipoprotein lipase deficiency.

Atherosclerosis. 2016 Aug 21;:

Authors: Steinhagen-Thiessen E, Stroes E, Soran H, Johnson C, Moulin P, Iotti G, Zibellini M, Ossenkoppele B, Dippel M, Averna MR, GENIALL Investigators

Abstract
A good understanding of the natural history of rare genetic lipid disorders is a pre-requisite for successful patient management. Disease registries have been helpful in this regard. Lipoprotein Lipase Deficiency (LPLD) is a rare, autosomal-recessive lipid disorder characterized by severe hypertriglyceridemia and a very high risk for recurrent acute pancreatitis, however, only limited data are available on its natural course. Alipogene tiparvovec (Glybera(®)) is the first gene therapy to receive Marketing Authorization in the European Union; GENIALL (GENetherapy In the MAnagement of Lipoprotein Lipase Deficiency), a 15-year registry focusing on LPLD was launched in 2014 as part of its Risk Management Plan. The aim of this publication is to introduce the GENIALL Registry within a structured literature review of registries in rare genetic lipid disorders. A total of 11 relevant initiatives/registries were identified (homozygous Familial Hypercholesterolemia (hoFH) [n = 5]; LPLD [n = 1]; Lysosomal Acid Lipase Deficiency [LALD, n = 1], detection of mutations in genetic lipid disorders [n = 4]). Besides one product registry in hoFH and the LALD registry, all other initiatives are local or country-specific. GENIALL is the first global prospective registry in LPLD that will collect physician and patient generated data on the natural course of LPLD, as well as long-term outcomes of gene therapy.
CONCLUSION: There is a limited number of international initiatives focusing on the natural course of specific rare genetic lipid disorders. The GENIALL LPLD Registry could be the first step towards a future broader global initiative that collects data related to familial chylomicronemia syndrome and their underlying genetic causes.

PMID: 28284702 [PubMed - as supplied by publisher]

Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU.

Hum Genet. 2017 Mar 10;:

Authors: Depienne C, Nava C, Keren B, Heide S, Rastetter A, Passemard S, Chantot-Bastaraud S, Moutard ML, Agrawal PB, VanNoy G, Stoler JM, Amor DJ, Billette de Villemeur T, Doummar D, Alby C, Cormier-Daire V, Garel C, Marzin P, Scheidecker S, de Saint-Martin A, Hirsch E, Korff C, Bottani A, Faivre L, Verloes A, Orzechowski C, Burglen L, Leheup B, Roume J, Andrieux J, Sheth F, Datar C, Parker MJ, Pasquier L, Odent S, Naudion S, Delrue MA, Le Caignec C, Vincent M, Isidor B, Renaldo F, Stewart F, Toutain A, Koehler U, Häckl B, von Stülpnagel C, Kluger G, Møller RS, Pal D, Jonson T, Soller M, Verbeek NE, van Haelst MM, de Kovel C, Koeleman B, Monroe G, van Haaften G, DDD Study, Attié-Bitach T, Boutaud L, Héron D, Mignot C

Abstract
Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.

PMID: 28283832 [PubMed - as supplied by publisher]

Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation.

Cell. 2017 Mar 09;168(6):1053-1064.e15

Authors: Kim AR, Ulirsch JC, Wilmes S, Unal E, Moraga I, Karakukcu M, Yuan D, Kazerounian S, Abdulhay NJ, King DS, Gupta N, Gabriel SB, Lander ES, Patiroglu T, Ozcan A, Ozdemir MA, Garcia KC, Piehler J, Gazda HT, Klein DE, Sankaran VG

Abstract
Cytokines are classically thought to stimulate downstream signaling pathways through monotonic activation of receptors. We describe a severe anemia resulting from a homozygous mutation (R150Q) in the cytokine erythropoietin (EPO). Surprisingly, the EPO R150Q mutant shows only a mild reduction in affinity for its receptor but has altered binding kinetics. The EPO mutant is less effective at stimulating erythroid cell proliferation and differentiation, even at maximally potent concentrations. While the EPO mutant can stimulate effectors such as STAT5 to a similar extent as the wild-type ligand, there is reduced JAK2-mediated phosphorylation of select downstream targets. This impairment in downstream signaling mechanistically arises from altered receptor dimerization dynamics due to extracellular binding changes. These results demonstrate how variation in a single cytokine can lead to biased downstream signaling and can thereby cause human disease. Moreover, we have defined a distinct treatable form of anemia through mutation identification and functional studies.

PMID: 28283061 [PubMed - in process]

Splenic rupture and mediastinal mass associated with rare TdT-negative T-LBL/T-ALL lead to sudden death of a juvenile.

Forensic Sci Med Pathol. 2016 Dec;12(4):523-526

Authors: Gascho D, Huber B, Bolliger SA, Thali MJ, Schaerli S

PMID: 27778145 [PubMed - indexed for MEDLINE]

An extreme case of platypnoea-orthodeoxia syndrome.

Clin Med (Lond). 2016 Oct;16(5):453-454

Authors: O'Gallagher K, Chou E, Jeyabraba S, Sinha A, Robb D, Byrne J

Abstract
An 80-year-old female presented with progressive breathlessness, worse on sitting or standing and relieved by lying flat. Subsequent investigations identified a patent foramen ovale (PFO) with right-to-left flow across the interatrial septum (IAS). A diagnosis of platypnoea orthodeoxia syndrome secondary to inter-atrial shunting was made. Technical features precluded a percutaneous PFO closure so an open surgical repair was performed with complete resolution of symptoms. We discuss the pathophysiology and management of platypnoea orthodeoxia syndrome.

PMID: 27697809 [PubMed - indexed for MEDLINE]

The International Hypothermia Registry (IHR): Dieter's ESAO Winter Schools and Beat's International Hypothermia Registry.

Int J Artif Organs. 2017 Mar 07;40(1):40-42

Authors: Walpoth BH, Meyer M, Gaudet-Blavignac C, Baumann P, Gilquin P, Lovis C

Abstract
Accidental hypothermia could be listed as an 'orphan disease,' since mild hypothermia is common but has no severe medical consequences, whereas severe hypothermia is rare and life-threatening. In order to increase our knowledge, find new outcome predictors, and propose better guidelines for the treatment of deep accidental hypothermia victims, we created the International Hypothermia Registry (IHR: https://www.hypothermia-registry.org), which will allow us to gather a large number of cases in order to achieve statistical significance and issue evidence-based recommendations.

PMID: 28277601 [PubMed - as supplied by publisher]

Mandibular melanotic neuroectodermal tumor of infancy: a role for neoadjuvant chemotherapy.

Eur Arch Otorhinolaryngol. 2016 Dec;273(12):4629-4635

Authors: Maroun C, Khalifeh I, Alam E, Akl PA, Saab R, Moukarbel RV

Abstract
Melanotic Neuroectodermal Tumor of Infancy (MNTI) is a rare, locally aggressive neoplasm with a predilection for the head and neck area, most commonly occurring in the maxilla. The vast majority of treatment modalities for all cases of MNTI to date have involved surgical intervention only, with just 9.6 % involving some sort of chemotherapy, radiotherapy, or a combination of the prior mentioned modalities. There is very limited information available regarding the use of neoadjuvant chemotherapy, due to its rare nature. In this report, a 4 month old girl presented to our clinic with a chief complaint of a large oral mass of about 2.5 months in duration. Intraoral examination showed an oral mass arising from the lingual aspect of inferior alveolar ridge with extensive mandibular invasion. The patient received three cycles of vincristine, Adriamycin, and cyclophosphamide as neodajuvant therapy. Upon completion, the tumor had decreased significantly in size. The patient was then scheduled for surgery and underwent surgical resection of the tumor. We were able to obtain adequate shrinkage of the tumor to allow better resectability, easier surgical access and a more minimally invasive approach with no lip split and a smaller neck incision. In conclusion, we have reported an extremely rare case of MNTI of the mandible that was successfully treated with neoadjuvant chemotherapy and surgical resection. This approach was advantageous to minimize the chance of recurrence and improve resectability in particularly large tumors, while maximizing functional outcomes and minimizing deformity.

PMID: 27107579 [PubMed - indexed for MEDLINE]

Signaling through RNA-binding proteins as a cell fate regulatory mechanism.

Cell Cycle. 2017 Mar 08;:0

Authors: Tsanov KM, Daley GQ

PMID: 28272977 [PubMed - as supplied by publisher]

Schwannoma of the Recurrent Laryngeal Nerve: A Rare Entity.

Innovations (Phila). 2017 Jan/Feb;12(1):64-66

Authors: de Heer LM, Teding van Berkhout F, Priesterbach-Ackley LP, Buijsrogge MP

Abstract
Neurogenic tumors are the most common posterior mediastinal tumors in adults. Schwannomas originating from the recurrent laryngeal nerve are rare. The present study describes a 46-year-old man with a tumor in the left superior mediastinum. Because of the narrow relationship with the aorta and the left pulmonary artery, the tumor was excised by left-sided minithoracotomy. The tumor, a schwannoma, originated from and encased the left recurrent laryngeal nerve. Six months after surgery, the patient was free of recurrence without symptoms other than hoarseness. "Additional imaging by magnetic resonance imaging could raise the probability of a neurogenic origin of the mass, eventually leading to collaboration with the neurosurgeon in this case."

PMID: 28085688 [PubMed - indexed for MEDLINE]

Urothelial neoplasm of the bladder in childhood and adolescence: a rare disease.

Int Braz J Urol. 2016 Mar-Apr;42(2):242-6

Authors: Polat H, Utangac MM, Gulpinar MT, Cift A, Erdogdu IH, Turkcu G

Abstract
PURPOSE: Bladder tumors are rare in children and adolescents. For this reason, the diagnosis is sometimes delayed in pediatric patients. We aimed to describe the diagnosis, treatment, and follow-up methods of bladder urothelial neoplasms in children and adolescents.
MATERIALS AND METHODS: We carried out a retrospective multicenter study involving patients who were treated between 2008 and 2014. Eleven patients aged younger than 18 years were enrolled in the study. In all the patients, a bladder tumor was diagnosed using ultrasonography and was treated through transurethral resection of the bladder (TURBT).
RESULTS: Nine of the 11 patients (82%) were admitted with gross hematuria. The average delay in diagnosis was 3 months (range, 0-16 months) until the ultrasonographic diagnosis was performed from the first episodes of macroscopic hematuria. A single exophytic tumor (1-4cm) was present in each patient. The pathology of all patients was reported as superficial urothelial neoplasm: two with papilloma, one with papillary urothelial neoplasm of low malignant potential (PUNLMP), four with low grade pTa, and four with low grade pT1. No recurrence was observed during regular cystoscopic and ultrasonographic follow-up.
CONCLUSIONS: Regardless of the presence of hematuria, bladder tumors in children are usually not considered because urothelial carcinoma in this population is extremely rare, which causes a delay in diagnosis. Fortunately, the disease has a good prognosis and recurrences are infrequent. Cystoscopy may be unnecessary in the follow-up of children with bladder tumors. We believe that ultrasonography is sufficient in follow-up.

PMID: 27256177 [PubMed - indexed for MEDLINE]

[Spiradenocarcinoma of the forehead : A rare skin tumor in the head and neck region].

HNO. 2016 May;64(5):328-30

Authors: Schwarz D, Göbel H, Gostian AO, Meyer MF, Anagiotos A

Abstract
Spiradenocarcinomas are rare malignant tumors that originate from the sweat glands of the skin and demonstrate aggressive growth. We report the case of an 86-year-old female patient presenting with a growth on the forehead which had been apparent for 2 years. After surgical removal of the tumor, histological workup culminated in the diagnosis of a spiradenocarcinoma. Surgical margins were free of tumor on pathological examination. Metastasis was excluded by positron-emission tomography-computed tomography (PET-CT). Due to the advanced age of the patient and the absence of metastatic disease, no adjuvant therapy was performed. Six months postoperatively there is no evidence of relapse.

PMID: 26231725 [PubMed - indexed for MEDLINE]

Eventration of the Right Hemidiaphragm with Resultant Right Atrial Compression-A Rare Finding.

Echocardiography. 2016 Sep;33(9):1432-3

Authors: Lau GT, To AC

PMID: 27247197 [PubMed - indexed for MEDLINE]

Attention Should be Drawn to Rare Diseases and Interpretation of Sequence Variants.

Chin Med J (Engl). 2016 May 05;129(9):1009-10

Authors: Tang BS

PMID: 27098782 [PubMed - indexed for MEDLINE]

Can the EVIDEM Framework Tackle Issues Raised by Evaluating Treatments for Rare Diseases: Analysis of Issues and Policies, and Context-Specific Adaptation.

Pharmacoeconomics. 2016 Mar;34(3):285-301

Authors: Wagner M, Khoury H, Willet J, Rindress D, Goetghebeur M

Abstract
BACKGROUND: The multiplicity of issues, including uncertainty and ethical dilemmas, and policies involved in appraising interventions for rare diseases suggests that multicriteria decision analysis (MCDA) based on a holistic definition of value is uniquely suited for this purpose. The objective of this study was to analyze and further develop a comprehensive MCDA framework (EVIDEM) to address rare disease issues and policies, while maintaining its applicability across disease areas.
METHODS: Specific issues and policies for rare diseases were identified through literature review. Ethical and methodological foundations of the EVIDEM framework v3.0 were systematically analyzed from the perspective of these issues, and policies and modifications of the framework were performed accordingly to ensure their integration.
RESULTS: Analysis showed that the framework integrates ethical dilemmas and issues inherent to appraising interventions for rare diseases but required further integration of specific aspects. Modification thus included the addition of subcriteria to further differentiate disease severity, disease-specific treatment outcomes, and economic consequences of interventions for rare diseases. Scoring scales were further developed to include negative scales for all comparative criteria. A methodology was established to incorporate context-specific population priorities and policies, such as those for rare diseases, into the quantitative part of the framework. This design allows making more explicit trade-offs between competing ethical positions of fairness (prioritization of those who are worst off), the goal of benefiting as many people as possible, the imperative to help, and wise use of knowledge and resources. It also allows addressing variability in institutional policies regarding prioritization of specific disease areas, in addition to existing uncertainty analysis available from EVIDEM.
CONCLUSION: The adapted framework measures value in its widest sense, while being responsive to rare disease issues and policies. It provides an operationalizable platform to integrate values, competing ethical dilemmas, and uncertainty in appraising healthcare interventions.

PMID: 26547306 [PubMed - indexed for MEDLINE]

Lhermitte-Duclos disease associated to Cowden syndrome: de novo diagnosis and management of these extremely rare syndromes in a patient.

BMJ Case Rep. 2017 Jan 30;2017:

Authors: Gama I, Almeida L

Abstract
A 36-year-old woman, with history of cutaneous papilomatosis and thyroid carcinoma presented with headache, transitory visual blurring and nausea. Funduscopy showed papilloedema. MRI showed a tumour of the right cerebellar hemisphere with a striated, tigroid pattern, typical of Lhermitte-Duclos disease (LDD). Significant clinical and perimetric improvements were noted after surgery and the follow-up did not reveal recurrences of the tumour. LDD is an extremely rare differential diagnosis of posterior fossa tumours. LDD and the history of thyroid carcinoma permitted us to diagnose Cowden syndrome (CS). We present a clinical case that supports the possibility of performing a preoperative diagnosis of LDD based on MRI features. We review the diagnosis and management of LDD and CS. This report highlights the importance of excluding CS after LDD diagnosis, of monitoring the optic nerve postoperatively using optical coherence tomography and of prompt treatment that can potentially prevent visual function loss.

PMID: 28137902 [PubMed - indexed for MEDLINE]

TB or not to be? Kikuchi-Fujimoto disease: a rare but important differential for TB.

BMJ Case Rep. 2017 Jan 04;2017:

Authors: McKenna C, Whitfield T, Patel N, Bonington A

Abstract
A 29-year-old British Pakistani woman presented with a 2-month history of drenching fevers, night sweats, lethargy and tender cervical and axillary lymphadenopathy. Initial investigations, bloods and imaging were unremarkable. Fever persisted during her admission, and treatment for tuberculosis (TB) lymphadenitis was started postbiopsy until histology confirmed a diagnosis of Kikuchi-Fujimoto's disease (KFD). KFD has a non-specific presentation of fever, night sweats and lymphadenopathy and commonly raises a clinical suspicion of a number of other serious conditions such as TB, lymphoma, HIV, systemic lupus erythematous, toxoplasmosis and infectious mononucleosis. Although rare, KFD should be considered to be a differential diagnosis for fever of unknown origin and tender lymphadenopathy in otherwise well individuals. This case demonstrates the importance of a timely histological biopsy diagnosis to prevent an incorrect diagnosis and administration of unnecessary medications.

PMID: 28052948 [PubMed - indexed for MEDLINE]

Primitive neuroectodermal tumour of the cervix: a rare diagnosis.

BMJ Case Rep. 2017 Jan 04;2017:

Authors: Ahmad I, Chufal KS, Bhargava A, Bashir I

Abstract
A 48-year-old woman presented with symptoms of lower abdominal pain and vaginal discharge for 6 months. Clinical examination and pelvic ultrasound scan suggested a diagnosis of infected Gartner's cyst, for which she underwent vaginal cystectomy. However, histopathology and immunohistochemistry revealed a diagnosis of primitive neuroectodermal tumour of the cervix. Further investigations revealed the stage to be FIGO IIIB, which was inoperable. She received neoadjuvant chemotherapy (vincristine, adriamycin, cyclophosphamide alternating with ifosfamide, cisplatin and etoposide, every 21 days), but the tumour did not respond to treatment and she was started on radiotherapy with definitive intent (55.8 Gray in 31 fractions over 6.2 weeks). A PET-CT performed 2 months after completion of radiotherapy showed complete response, and she is now receiving adjuvant chemotherapy.

PMID: 28052947 [PubMed - indexed for MEDLINE]

Drug repositioning in sarcomas and other rare tumors.

EBioMedicine. 2016 Apr;6:4-5

Authors: Lee AT, Huang PH, Pollack SM, Jones RL

PMID: 27211532 [PubMed - indexed for MEDLINE]

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Biallelic mutations in human DCC cause developmental split-brain syndrome.

Nat Genet. 2017 Feb 27;:

Authors: Jamuar SS, Schmitz-Abe K, D'Gama AM, Drottar M, Chan WM, Peeva M, Servattalab S, Lam AN, Delgado MR, Clegg NJ, Zayed ZA, Dogar MA, Alorainy IA, Jamea AA, Abu-Amero K, Griebel M, Ward W, Lein ES, Markianos K, Barkovich AJ, Robson CD, Grant PE, Bosley TM, Engle EC, Walsh CA, Yu TW

Abstract
Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a new human syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported. Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis. Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white-matter projections throughout the human CNS.

PMID: 28250456 [PubMed - as supplied by publisher]