Identification of a novel CNTNAP1 mutation causing arthrogryposis multiplex congenita with cerebral and cerebellar atrophy.

Eur J Med Genet. 2017 May;60(5):245-249

Authors: Lakhani S, Doan R, Almureikhi M, Partlow JN, Al Saffar M, Elsaid MF, Alaaraj N, James Barkovich A, Walsh CA, Ben-Omran T

Abstract
Arthrogryposis multiplex congenital, the occurrence of multiple joint contractures at birth, can in some cases be accompanied by insufficient myelination of peripheral nerves, muscular hypotonia, reduced tendon reflexes, and respiratory insufficiency. Recently mutations in the CASPR/CNTN1 complex have been associated with similar severe phenotypes and CNTNAP1 gene mutations, causing loss of the CASPR protein, were shown to cause severe, prenatal onset arthrogryposis multiplex congenita in four unrelated families. Here we report a consanguineous Arab family from Qatar with three children having an early lethal form of arthrogryposis multiplex congenita and a novel frameshift mutation in CNTNAP1. We further expand the existing CNTNAP1-associated phenotype to include profound cerebral and cerebellar atrophy.

PMID: 28254648 [PubMed - indexed for MEDLINE]

[Renovascular disease in children - a rare diagnosis with few symptoms].

Tidsskr Nor Laegeforen. 2017 Feb;137(4):279-282

Authors: Thorsteinsdottir H, Dorenberg E, Line PD, Bjerre A

Abstract
BACKGROUND To estimate the prevalence, symptoms, causes and treatment of renovascular disease in children, and also to assess the degree of secondary organ damage to the heart, kidneys and eyes (end organ damage).MATERIAL AND METHOD Retrospective review of data for all children (0 - 16 years) who were examined for resistant hypertension in the period 1998 - 2013 at Oslo University Hospital Rikshospitalet.RESULTS A total of 21 children/adolescents (median age 8.5 years, 11 girls) were assessed and treated for resistant hypertension in the study period. Altogether had 38 % no symptoms at the time of diagnosis and 19 % had classical symptoms of hypertension. Fifteen patients received invasive treatment in the form of percutaneous transluminal renal angioplasty (PTRA) (n = 5), nephrectomy (n = 6), coiling (n = 1), autotransplantation (n = 1) or a combination of these (n = 2). Blood pressure improved following treatment in 10 of 14 patients for whom outcomes were recorded in the medical records. End organ damage to the heart and retina was observed in 60 % and 50 % of patients, respectively.INTERPRETATION Children with severely elevated blood pressure as a result of renovascular disease often have unspecific or no symptoms. Blood pressure improved following invasive treatment in 10 of 14 children and few complications were recorded. Invasive treatment may be considered in children and adolescents when standard treatment for hypertension is insufficient.

PMID: 28225234 [PubMed - indexed for MEDLINE]

Congenital lobar emphysema: diagnostic and therapeutic challenges.

BMJ Case Rep. 2016 Jun 22;2016:

Authors: Mulvany JJ, Weatherall A, Charlton A, Selvadurai H

Abstract
Congenital lobar emphysema (CLE), a rare condition that usually presents in the neonatal period, can be a diagnostic and therapeutic challenge for the treating clinician. If unrecognised, it is a significant risk at the time of anaesthetic induction. We describe a case of CLE in a 3-month-old boy who was initially treated for suspected aspiration pneumonia at the referring hospital. We highlight the importance of careful consideration of common childhood respiratory illness as well as pneumothorax in the differential diagnosis, and the significance of appropriate preoperative anaesthetic management. We also emphasise the importance of acknowledging a mother's concerns when taking a paediatric history.

PMID: 27335360 [PubMed - indexed for MEDLINE]

Biology and management of clear cell sarcoma: state of the art and future perspectives.

Expert Rev Anticancer Ther. 2016 Aug;16(8):839-45

Authors: Cornillie J, van Cann T, Wozniak A, Hompes D, Schöffski P

Abstract
INTRODUCTION: Clear cell sarcoma (CCS) is an aggressive tumor, typically developing in tendons or aponeuroses. The outcome of this orphan disease is poor, with 5-year and 10-year survival rates of localized CCS around 60-70% and 40-50%. Once the disease has metastasized, it is usually fatal due to its chemotherapy-resistant nature. Systemic treatment options are poorly standardized and the use of chemotherapy is based on weak scientific evidence.
AREAS COVERED: In this review, we systematically discuss the current scientific evidence for the systemic treatment of CCS, including tyrosine kinase inhibitors, immunotherapy and MET inhibitors. Expert commentary: Recent insights in the biology of CCS have identified new potential therapeutic targets, which should be tested in prospective clinical trials. Whenever possible, patients with metastatic CCS should be included in clinical trials with good biological rationale. Innovative trial methodology and new regulatory mechanisms are required to provide patients with uncommon cancers with active drugs.

PMID: 27253849 [PubMed - indexed for MEDLINE]

Three Cases of Erdheim-Chester Disease With Intraocular Manifestations: Imaging and Histopathology Findings of a Rare Entity.

Am J Ophthalmol. 2017 Apr;176:141-147

Authors: Tan AC, Yzer S, Atebara N, Marr BP, Verdijk RM, Dalm VA, Freund KB, Yannuzzi L, Missotten T

Abstract
PURPOSE: To report intraocular manifestations of Erdheim-Chester Disease (ECD) with multimodal imaging.
DESIGN: A retrospective observational case series.
METHODS: This was a multicenter case series of 3 patients with confirmed tissue diagnosis of ECD that showed intraocular manifestations and were imaged at baseline and follow-up visits.
RESULTS: Intraocular manifestations are rarely observed in association with ECD. Intraocular manifestations of ECD seen on multimodal imaging include histiocytic choroidal infiltration causing choroidal lesions, complicated by recurrent serous retinal detachment (SRD). Short-term resolution of SRD was observed with ocular therapies including intravitreal injections of anti-vascular endothelial growth factor or verteporfin photodynamic therapy in combination with systemic chemotherapy therapies and oral corticosteroids; however, recurrences were common. Chorioretinal biopsy confirmed the diagnosis of ECD in 1 case, with the presence of histiocytic infiltration, fibrosis, and characteristic immunohistologic staining. In another case, with a novel ARAF positive mutation, treatment with sorafenib showed regression of the choroidal lesions and resolution of the SRD on multimodal imaging. These lesions were previously resistant to other forms of therapy.
CONCLUSIONS: Rare intraocular manifestations of ECD confirmed on histopathology can be imaged with multimodal imaging. We report 3 cases, including 1 case diagnosed through histology from chorioretinal biopsy and another case associated with a novel ARAF mutation responsive to targeted therapy with sorafenib. The identification of novel somatic mutation associated with ECD enabled treatment with a new-targeted systemic agent. Multimodal imaging in these cases can also be used to monitor response to therapy.

PMID: 28153505 [PubMed - indexed for MEDLINE]

Perforation With Submucosal Cleft Palate in a Previously Undiagnosed Adult Patient.

J Craniofac Surg. 2016 Oct;27(7):e659-e661

Authors: Evin ŞG, Karamese M, Akdag O, Selimoglu MN, Tosun Z

Abstract
Perforation with a submucosal cleft palate (SMCP) is a rare condition with a limited number of cases reported in the literature. However, most described cases include neonates and infants, but not cases due to trauma or infection. Here, we present a case of an adult patient with SMCP with a perforation of the palate who was undiagnosed. In light of this case, diagnosis and treatment of perforation in SMCP are presented. A new diagram that can be used in the management of these patients with velopharyngeal insufficiency is proposed.

PMID: 27526237 [PubMed - indexed for MEDLINE]

Pharmacotherapy of inborn errors of metabolism illustrating challenges in orphan diseases.

J Pharmacol Toxicol Methods. 2016 Sep-Oct;81:9-14

Authors: Das AM

Abstract
Orphan diseases (OD) have special challenges based on the rarity of the conditions. Mostly multicentre studies are required, controlled studies are difficult to perform. Based on the often chronic course of OD with slow progress the effect of therapeutic interventions is difficult to assess. Development and production of pharmaceutical substances for OD is difficult, time-consuming and sophisticated. Special incentives by the regulatory bodies like protocol assistance, long marketing exclusivity and reduced licencing fees encourage the development of orphan drugs. Inborn errors of metabolism (IEMs) due to enzyme or transporter deficiencies are taken as an example for OD. Accumulation of substrates proximal to the deficient enzyme during catabolic episodes leads to autointoxication with acute onset of symptoms. IEMs due to transporter deficiency usually have a more stable, chronic course. Therapeutic options are substrate reduction by diet or drugs, vitamin/cofactor supplementation, enzyme replacement, enzyme augmentation and transplantation of organs or cells. Phenylketonuria (PKU) is the prototype of an IEM which can be successfully treated by diet. The outcome of hepatorenal tyrosinaemia type 1 was revolutionarized by substrate reduction using nitisinone (NTBC) which was discovered by chance. Lysosomal storage diseases are examples where enzyme replacement therapy is successful. Enzyme augmentation can be achieved in some IEM-patients with a mild phenotype (residual enzyme activity) by chaperones which stabilize the enzyme. Organ transplantation is an option in those patients who cannot be managed by drugs and/or diet. Bone marrow transplantation is successful in some patients where CNS-involvement occurs. The CNS cannot be reached by enzyme replacement therapy (blood-brain barrier). While safety and efficacy of drugs for OD have been demonstrated pre-marketing, post-marketing surveys are often necessary to include more patients.

PMID: 26921514 [PubMed - indexed for MEDLINE]

Metachronous gallbladder metastasis from renal cell carcinoma-a rare clinical manifestation.

Wien Klin Wochenschr. 2016 Sep;128(17-18):669-71

Authors: Mrak K, Lackner C, Mischinger HJ, Kornprat P

Abstract
Renal cell carcinoma (RCC) represents a rare tumor entity accounting for approximately 3 % of all malignancies in the adult population. Approximately 30 % of all patients suffering from RCC develop metastases after nephrectomy and another 30 % of patients suffer from synchronous metastases at the date of diagnosis. Gallbladder metastases represent an extremely rare clinical condition and up to date there are only 35 published cases of gallbladder metastasis from RCC. Surgical resection should be the treatment of choice in any case based on the reported data in literature. In spite of the small series of cases, survival can be improved even in patients suffering from additional sites of metastases.

PMID: 27624324 [PubMed - indexed for MEDLINE]

First report of otitis externa caused by Schizophyllum commune and review of the literature.

Wien Klin Wochenschr. 2016 May;128(9-10):387-90

Authors: Matos T, Tomazin R, Battelino S

Abstract
Basidiomycete Schizophyllum commune is a widely distributed cellulolytic fungus that is a well-known pathogen. It can cause a wide range of different infections, and here we describe the first case of otitis externa and a molecularly based identification process.

PMID: 26802032 [PubMed - indexed for MEDLINE]

The Undiagnosed Diseases Network: Accelerating Discovery about Health and Disease.

Am J Hum Genet. 2017 Feb 02;100(2):185-192

Authors: Ramoni RB, Mulvihill JJ, Adams DR, Allard P, Ashley EA, Bernstein JA, Gahl WA, Hamid R, Loscalzo J, McCray AT, Shashi V, Tifft CJ, Undiagnosed Diseases Network, Wise AL

Abstract
Diagnosis at the edges of our knowledge calls upon clinicians to be data driven, cross-disciplinary, and collaborative in unprecedented ways. Exact disease recognition, an element of the concept of precision in medicine, requires new infrastructure that spans geography, institutional boundaries, and the divide between clinical care and research. The National Institutes of Health (NIH) Common Fund supports the Undiagnosed Diseases Network (UDN) as an exemplar of this model of precise diagnosis. Its goals are to forge a strategy to accelerate the diagnosis of rare or previously unrecognized diseases, to improve recommendations for clinical management, and to advance research, especially into disease mechanisms. The network will achieve these objectives by evaluating patients with undiagnosed diseases, fostering a breadth of expert collaborations, determining best practices for translating the strategy into medical centers nationwide, and sharing findings, data, specimens, and approaches with the scientific and medical communities. Building the UDN has already brought insights to human and medical geneticists. The initial focus has been on data sharing, establishing common protocols for institutional review boards and data sharing, creating protocols for referring and evaluating patients, and providing DNA sequencing, metabolomic analysis, and functional studies in model organisms. By extending this precision diagnostic model nationally, we strive to meld clinical and research objectives, improve patient outcomes, and contribute to medical science.

PMID: 28157539 [PubMed - indexed for MEDLINE]

Ovarian cancer in children and adolescents: A rare disease that needs more attention.

Maturitas. 2016 Jun;88:3-8

Authors: Baert T, Storme N, Van Nieuwenhuysen E, Uyttebroeck A, Van Damme N, Vergote I, Coosemans A

Abstract
Ovarian cancer is rare in childhood. This explains why there are only scattered reports on it in the literature and why there is a lack of specific pediatric treatment. This paper gives an overview of the Belgian data from 2004 to 2013 and reviews the literature. To index ovarian masses and malignancies in children better in the future, worldwide data collection should be improved and reproducible definitions of 'childhood', 'malignancy' and 'ovarian mass' need to be adopted.

PMID: 27105689 [PubMed - indexed for MEDLINE]

Hereditary Multiple Exostoses: New Insights into Pathogenesis, Clinical Complications, and Potential Treatments.

Curr Osteoporos Rep. 2017 May 02;:

Authors: Pacifici M

Abstract
PURPOSE OF REVIEW: Hereditary multiple exostoses (HME) is a complex musculoskeletal pediatric disorder characterized by osteochondromas that form next to the growth plates of many skeletal elements, including long bones, ribs, and vertebrae. Due to its intricacies and unresolved issues, HME continues to pose major challenges to both clinicians and biomedical researchers. The purpose of this review is to describe and analyze recent advances in this field and point to possible targets and strategies for future biologically based therapeutic intervention.
RECENT FINDINGS: Most HME cases are linked to loss-of-function mutations in EXT1 or EXT2 that encode glycosyltransferases responsible for heparan sulfate (HS) synthesis, leading to HS deficiency. Recent genomic inquiries have extended those findings but have yet to provide a definitive genotype-phenotype correlation. Clinical studies emphasize that in addition to the well-known skeletal problems caused by osteochondromas, HME patients can experience, and suffer from, other symptoms and health complications such as chronic pain and nerve impingement. Laboratory work has produced novel insights into alterations in cellular and molecular mechanisms instigated by HS deficiency and subtending onset and growth of osteochondroma and how such changes could be targeted toward therapeutic ends. HME is a rare and orphan disease and, as such, is being studied only by a handful of clinical and basic investigators. Despite this limitation, significant advances have been made in the last few years, and the future bodes well for deciphering more thoroughly its pathogenesis and, in turn, identifying the most effective treatment for osteochondroma prevention.

PMID: 28466453 [PubMed - as supplied by publisher]

Balloon-Occluded Retrograde Transvenous Obliteration of a Gastric Vascular Malformation: An Innovative Approach to Treatment of a Rare Condition.

Cardiovasc Intervent Radiol. 2017 Feb;40(2):310-314

Authors: Hansing CE, Marquardt JP, Sutton DM, York JD

Abstract
Arteriovenous malformations (AVMs) are a high-flow form of a vascular malformation, which can be found anywhere in the body. While historically treated surgically, a multidisciplinary approach utilizing multiple specialties and treatment modalities is now commonly employed. In order to effectively treat an AVM, the nidus must be targeted and eradicated, which can be done via multiple approaches. We present the case of a 43-year-old male with a gastric wall AVM, which was initially incompletely treated using a percutaneous transarterial approach. The gastric AVM was noted to have dominant drainage through a gastrorenal shunt; therefore, Balloon-occluded Retrograde Transvenous Obliteration (BRTO) was utilized to eradicate the AVM nidus. This case illustrates the utility of Interventional Radiology, specifically BRTO, as another treatment option for challenging AVMs.

PMID: 27671152 [PubMed - indexed for MEDLINE]

[A rare pulmonary tumor: Primary carcinosarcoma of the lung].

Rev Pneumol Clin. 2016 Dec;72(6):381-384

Authors: Mjid M, Toujani S, Blibech H, Hedhli A, Ouahchi Y, Haouet S, Cherif J, Beji M

PMID: 27789162 [PubMed - indexed for MEDLINE]

[Azygos vein aneurysm: An unusual and rare diagnostic].

Rev Pneumol Clin. 2016 May;72(3):217-9

Authors: Alberti N, Petitpierre F, Crombe A, Bernard S, Sironneau S

PMID: 27133177 [PubMed - indexed for MEDLINE]

Novel mutation in CNTNAP1 results in congenital hypomyelinating neuropathy.

Muscle Nerve. 2017 May;55(5):761-765

Authors: Mehta P, Küspert M, Bale T, Brownstein CA, Towne MC, De Girolami U, Shi J, Beggs AH, Darras BT, Wegner M, Piao X, Agrawal PB

Abstract
INTRODUCTION: Congenital hypomyelinating neuropathy (CHN) is a rare congenital neuropathy that presents in the neonatal period and has been linked previously to mutations in several genes associated with myelination. A recent study has linked 4 homozygous frameshift mutations in the contactin-associated protein 1 (CNTNAP1) gene with this condition.
METHODS: We report a neonate with CHN who was found to have absent sensory nerve and compound muscle action potentials and hypomyelination on nerve biopsy.
RESULTS: On whole exome sequencing, we identified a novel CNTNAP1 homozygous missense mutation (p.Arg388Pro) in the proband, and both parents were carriers. Molecular modeling suggests that this variant disrupts a β-strand to cause an unstable structure and likely significant changes in protein function.
CONCLUSIONS: This report links a missense CNTNAP1 variant to the disease phenotype previously associated only with frameshift mutations. Muscle Nerve 55: 761-765, 2017.

PMID: 27668699 [PubMed - indexed for MEDLINE]

Genetic variation among 82 pharmacogenes: The PGRNseq data from the eMERGE network.

Clin Pharmacol Ther. 2016 Aug;100(2):160-9

Authors: Bush WS, Crosslin DR, Owusu-Obeng A, Wallace J, Almoguera B, Basford MA, Bielinski SJ, Carrell DS, Connolly JJ, Crawford D, Doheny KF, Gallego CJ, Gordon AS, Keating B, Kirby J, Kitchner T, Manzi S, Mejia AR, Pan V, Perry CL, Peterson JF, Prows CA, Ralston J, Scott SA, Scrol A, Smith M, Stallings SC, Veldhuizen T, Wolf W, Volpi S, Wiley K, Li R, Manolio T, Bottinger E, Brilliant MH, Carey D, Chisholm RL, Chute CG, Haines JL, Hakonarson H, Harley JB, Holm IA, Kullo IJ, Jarvik GP, Larson EB, McCarty CA, Williams MS, Denny JC, Rasmussen-Torvik LJ, Roden DM, Ritchie MD

Abstract
Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE-PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of "precision medicine." The February 2015 eMERGE-PGx data release includes sequence-derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled Combined Annotation-Dependent Depletion score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.

PMID: 26857349 [PubMed - indexed for MEDLINE]

Desmoid-Type Fibromatosis: Who, When, and How to Treat.

Curr Treat Options Oncol. 2017 May;18(5):29

Authors: Martínez Trufero J, Pajares Bernad I, Torres Ramón I, Hernando Cubero J, Pazo Cid R

Abstract
OPINION STATEMENT: Desmoid-type fibromatosis is a sarcoma subtype that gathers some singular characteristics, making it a difficult challenge to face in clinical practice. Despite its excellent survival prognosis, these tumors may be unpredictable, ranging from an asymptomatic indolent course to persistent, local, and extended recurrences that significantly impair quality of life. Although surgery was initially considered the first elective treatment, collected published data during the past few years are now pointing to the "wait and see" approach as a reasonable initial strategy because many patients can live a long life with the disease without having symptoms. When symptoms appear or there is a risk of functional impairment, a wide spectrum of therapies (local and systemic) can be useful in improving symptoms and controlling the disease. Because of the low incidence of desmoid-type fibromatosis, there is scarce scientific evidence supporting any specific treatment. Nonetheless, if volumetric responses are needed, chemotherapy may be a reasonable early option. However, if long-term control of disease is desirable, hormonal therapy, NSAIDs, and TKIs are the likely treatments of choice. Recent new findings in the biologic development of these tumors, such as the role of Wnt/β-catenin dependent pathway, have shown that the prognostic information provided by specific CTNNB1 gene mutations and other genetic profiles can lead to better methods of selecting patients as candidates for other approaches. Based on recent research, the Notch pathway inhibition in DF is one of the most promising potential targets to explore. As an orphan disease, it is mandatory that as many patients as possible be included in clinical trials.

PMID: 28439797 [PubMed - in process]

Plasmablastic lymphoma: an atypical cutaneous presentation of a rare entity.

Dermatol Online J. 2016 May 15;22(5):

Authors: Mota F, Mesquita B, Carvalho S, Coelho A, Velho G, Lima M, Selores M

Abstract
Plasmablastic lymphoma is a very rare B-cell lymphoma typically associated with immunosuppression: It occurs primarily in the oral cavity, although some cases were reported in other organs and tissues.To date, only 10 cases of primary cutaneous plasmablastic lymphoma have been described. Clinically, primary cutaneous plasmablastic lymphoma presents as non-specific cutaneous lesions (purple nodules, erythematous infiltrated plaques). In previously described cases, as in this case, histology and immunohistochemistry are required to make the diagnosis. Owing to the rarity of this entity, there is no established therapy, which makes its management an individualized, patient-based decision.

PMID: 27617520 [PubMed - indexed for MEDLINE]

[Sternal fracture in growing children : A rare and often overlooked fracture? Documentation of four cases].

Unfallchirurg. 2016 Jul;119(7):570-4

Authors: Fichtel I, Fernandez FF, Wirth T

Abstract
BACKGROUND: Sternal fractures in childhood are rare. The aim of the study was to investigate the accident mechanism, the detection of radiological and sonographical criteria and consideration of associated injuries.
METHOD: In the period from January 2010 to December 2012 all inpatients and outpatients with sternal fractures were recorded according to the documentation.
RESULTS: A total of 4 children aged 5-14 years with a sternal fracture were treated in 2 years, 2 children were hospitalized for pain management and 2 remained in outpatient care.
CONCLUSION: Isolated sternal fractures in childhood are often due to typical age-related traumatic incidents. Ultrasonography is a useful diagnostic tool for fracture detection and radiography is the method of choice for visualization of the extent of the dislocation.

PMID: 25277731 [PubMed - indexed for MEDLINE]