[Rare syndromes in intensive care medicine : Presentation of two cases].

Med Klin Intensivmed Notfmed. 2016 Jun;111(5):400-6

Authors: Gierlinger A, Siostrzonek P, Reisinger J

Abstract
This article presents two cases of young women with spontaneous life-threatening bleeding events. Both had a history of gastrointestinal rupture or arterial dissection. Based on their medical history and genetic testing, Ehlers-Danlos syndrome (EDS) IV (vascular type) was diagnosed. In this very rare disorder which accounts for only 5 % of all EDS cases, fibroblasts synthesize reduced and abnormal procollagen type III. This is caused by mutations in the COL3A1 gene coding for type III procollagen. Life expectancy in these patients is significantly reduced. In many cases spontaneous arterial ruptures or dissections and organ ruptures are the first manifestations of this disease. More than 80 % of patients with EDS IV suffer from a severe complication before 40 years of age. Treatment options are very limited. Most important is to avoid invasive procedures (open surgery as well as endovascular interventions) because of its high morbidity and mortality. Celiprolol, a cardioselective β‑blocker, seems to have a beneficial effect by reducing the incidence of vascular complications.

PMID: 27259332 [PubMed - indexed for MEDLINE]

The promise of immunotherapy in anal squamous cell carcinoma: a novel approach for an orphan disease.

Clin Adv Hematol Oncol. 2017 Dec;15(12):968-961

Authors: Johnson B, Eng C

Abstract
An estimated 8200 men and women in the United States will receive a diagnosis of squamous cell carcinoma of the anal canal (SCCA) in 2017. Although SCCA is rare, accounting for 2.6% of gastrointestinal cancers, its incidence rate has been steadily increasing over the last few decades in the United States and around the world. More than 90% of cases of SCCA occur in the context of prior human papillomavirus (HPV) infection. To date, preventive vaccinations against HPV remain markedly underutilized. Most patients who have SCCA present with locoregional disease that is cured with chemoradiation. However, metastatic disease develops in 25% of patients. The management of metastatic SCCA is based on single-institutional case series, with no accepted consensus regarding standard of care. Given the complex interplay between the incorporation of HPV DNA into the host cell genome and the oncogenesis of SCCA, immunotherapeutic strategies have become a strong focus of research efforts regarding the management of SCCA. Recently, a phase 2 trial of an anti-programmed death 1 antibody for refractory SCCA has shown positive results. This review summarizes novel immunotherapies that are under active clinical investigation and describes their potential use in the management of metastatic SCCA.

PMID: 29315288 [PubMed - in process]

A Rare Case of Giant Basal Cell Carcinoma of the Abdominal Wall: Excision and Immediate Reconstruction with a Pedicled Deep Inferior Epigastric Artery Perforator (DIEP) Flap.

Am J Case Rep. 2017 Dec 04;18:1284-1288

Authors: Di Lorenzo S, Zabbia G, Corradino B, Tripoli M, Pirrello R, Cordova A

Abstract
BACKGROUND Basal cell carcinoma (BCC) greater than 5 cm in diameter is called giant basal cell carcinoma (GBCC), or super giant basal cell carcinoma if it has a diameter larger than 20 cm. Giant BCC only accounts for 0.5% of BCCs and super giant BCC is exceedingly rare. On account of their rarity, there are no established guidelines for GBCC treatment. CASE REPORT We describe a peculiar case of an 82-year-old woman with a GBCC carcinoma of the lower abdominal wall. The tumor was surgically removed with ipsilateral inguinal lymph nodes and the abdominal wall was reconstructed immediately with a pedicled deep inferior epigastric artery perforator (DIEP) flap. CONCLUSIONS Treatment of giant basal cell carcinoma is often difficult, especially in elderly patients with poor general health and multiple pathologies. The pedicled DIEP flap is rotated to cover the loss of substance without tension, and it is easy to harvest and transfer. This flap allowed a good result without local or systemic complication. We present this report as a reminder of the occasional occurrence of extremely aggressive BCCs. We believe that, especially for rare tumors like these, it is very useful for the entire scientific community to publish these cases and the therapeutic strategies used to treat them.

PMID: 29199268 [PubMed - indexed for MEDLINE]

A Rare Case of Bochdalek Hernia with Concomitant Para-Esophageal Hernia, Repaired Laparoscopically in an Octogenarian.

Am J Case Rep. 2017 Nov 29;18:1261-1265

Authors: Susmallian S, Raziel A

Abstract
BACKGROUND A Bochdalek hernia (BH) is a rare congenital condition consisting of a posterolateral defect in the diaphragm. A para-esophageal hernia (PEH) is a rare variant of hiatus hernia. BH and PEH may present with gastric volvulus or incarceration, requiring emergency treatment. Minimally invasive surgery is the preferred treatment, particularly for elderly patients and patients with comorbidities. The occurrence of BH with concomitant PEH is a very rare event. We describe a case of an octogenarian patient with BH and concomitant PEH treated laparoscopically. CASE REPORT An 81-year-old male patient, without significant comorbidities, presented with a two-month history of severe chest pain and vomiting after eating. Cardiological investigations ruled out cardiac ischemia, infarction, or other cardiovascular abnormalities. Chest and abdominal computed tomography (CT) imaging demonstrated a large diaphragmatic hernia, with the entire stomach in the left thorax. Laboratory results showed mild anemia and a low iron level. The patient underwent simultaneous laparoscopic repair of a BH and a PEH with mesh reinforcement without antireflux fundoplication. The patient's postoperative recovery was uneventful. CONCLUSIONS We have presented a rare case of BH with concomitant PEH in an octogenarian that was successfully treated with laparoscopic surgery. Although these two forms of hernia are a very rare association, this case report illustrates that the surgical approach should be individualized in each patient's case to ensure a successful surgical outcome. In this case, the decision was made to suture the diaphragmatic crura and reinforce the diaphragm repair with mesh, rather than by fundoplication.

PMID: 29184050 [PubMed - indexed for MEDLINE]

Lead-related infective endocarditis: Factors influencing early and long-term survival in patients undergoing transvenous lead extraction.

Heart Rhythm. 2017 Jan;14(1):43-49

Authors: Polewczyk A, Jacheć W, Tomaszewski A, Brzozowski W, Czajkowski M, Opolski G, Grabowski M, Janion M, Kutarski A

Abstract
BACKGROUND: Lead-related infective endocarditis (LRIE) is a serious infectious disease with uncertain prognosis.
OBJECTIVE: The purpose of this study was to evaluate the factors that influence survival in patients with LRIE undergoing transvenous lead extraction (TLE).
METHODS: Clinical data obtained from 500 consecutive patients with LRIE undergoing TLE in the reference center in the years 2006 to 2015 were retrospectively analyzed. We evaluated the effect of demographic, clinical, and procedure-related factors on 30-day and long-term survival (mean 3-year follow-up).
RESULTS: Analysis of 30-day survival after TLE revealed 19 deaths (3.8%), with long-term mortality (mean 3-year follow-up) of 29.3% (146 deaths). Multivariate analysis showed unfavorable effects of age (hazard ratio [HR] 1.056, 95% confidence interval [CI] 1.030-1.082); decreased left ventricular ejection fraction (HR 0.687, 95% CI 0.545-0.866); renal failure (HR 3.099, 95% CI 1.865-5.150); and presence of vegetation fragments remaining after TLE (HR 1.384, 95% CI 1.089-1.760). Log-rank test and Kaplan-Meier survival curves demonstrated statistically worse prognosis in patients with large vegetations (>2 cm) and with vegetation remnants. Better prognosis was associated with LRIE coexisting with generator pocket infection.
CONCLUSION: Long-term mortality in LRIE patients is still high. Factors that influence negatively on prognosis include large cardiac vegetations and their remnants after TLE. Such vegetations develop most frequently in patients with decreased left ventricular ejection fraction and renal failure. Probably, early detection of LRIE would tend to limit the formation of large vegetations that invade the adjacent cardiac structures.

PMID: 27725287 [PubMed - indexed for MEDLINE]

A practical approach to ichthyoses with systemic manifestations.

Clin Genet. 2017 Jun;91(6):799-812

Authors: Saral S, Vural A, Wollenberg A, Ruzicka T

Abstract
Inherited ichthyoses are rare disorders in terms of patient numbers, but abundant in terms of clinical-genetic subtypes. These disorders are often associated with severe systemic manifestations, in addition to significant medical, cosmetic and social problems. There are 17 subtypes of syndromic ichthyosis identified so far and most patients with these syndromes are living in countries with high consanguinity rates. Frequently, clinicians cannot make a definitive diagnosis and patients are not managed properly owing to the rarity and complexity of these disorders. These difficulties make this group of ichthyosis and the patients living with them 'orphan'. After skin and skin appendages, nervous system is the most frequently involved system in ichthyosis syndromes. Thus, association of ichthyosis with neurological symptoms provides an important clue for diagnosis. In this article, we aim to increase clinicians' comprehension of ichthyosis syndromes by providing a symptomatology-based approach based on this observation. Additionally, we provide a review of ichthyosis syndromes, with special emphasis on neurological symptoms, hoping to attract interest to this complicated field.

PMID: 27377997 [PubMed - indexed for MEDLINE]

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Trials and Tribulations: An Industry Perspective on Conducting Registrational Trials in Alpha-1 Antitrypsin Deficiency.

Ann Am Thorac Soc. 2016 Aug;13 Suppl 4:S374-7

Authors: Forshag MS

Abstract
Registrational trials in rare and orphan diseases present complexities related to the identification of subjects, recruitment, logistical hurdles incumbent with far-flung study sites, and end points that are often less well defined than are those used in more common illnesses. Alpha-1 antitrypsin deficiency is an orphan disease of genetic origin that carries the additional challenges of variable penetration and slow disease progression. Registrational trials of augmentation therapy using plasma-derived alpha-1 antitrypsin carry all of the above-noted burdens, as well as competition from commercially available augmentation therapy in many countries.

PMID: 27564675 [PubMed - indexed for MEDLINE]

Biological and molecular characterization of a rare case of cutaneous Richter syndrome.

Hematol Oncol. 2017 Dec;35(4):869-874

Authors: Reda G, Cassin R, Fabris S, Ciceri G, Fattizzo B, Sciumè M, Orofino N, Gianelli U, Neri A, Cortelezzi A

Abstract
Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia in a high-grade lymphoma usually presenting nodal and bone marrow involvement. Richter syndrome can be localized at extranodal sites including the gastrointestinal tract, lungs, and skin. Cutaneous RS is an extremely rare disease apparently showing a less aggressive course than common presentations. While nodal RS has been extensively investigated in literature, pathogenesis and prognosis of cutaneous RS are still partially unknown, even if a role of Epstein-Barr virus infection and p53 disruption has been suggested. Herein, we characterized the histopathological, immunohistochemical features and cytogenetics and molecular alterations of a case of cutaneous RS developed after 8 years chronic lymphocytic leukemia history. Moreover, we reviewed the literature reports concerning cutaneous RS and made a focus on biological patterns and prognostic implications.

PMID: 27400669 [PubMed - indexed for MEDLINE]

What does the arthropathy of alkaptonuria teach us about disease mechanisms in osteoarthritis and ageing of joints?

Rheumatology (Oxford). 2016 07;55(7):1151-2

Authors: Gallagher JA, Ranganath LR, Boyde A

PMID: 26712212 [PubMed - indexed for MEDLINE]

Philadelphia Chromosome Positive de novo Acute Myeloid Leukemia.

J Coll Physicians Surg Pak. 2016 Nov;26(11):100-102

Authors: Quraishi AM, Akram M, Saeed S, Tahir M

Abstract
Philadelphia chromosome positive de novoacute myeloid leukemia (AML)is a rare disease with reported incidence of less than 1% of newly diagnosed cases of AML. Outcome of the disease is poor, owing to its resistance to conventional chemotherapy and variable response to imatinib besylate. We report a case of 24-year man who reported to our unit in November 2014 and was treated with conventional induction and consolidation chemotherapy with imatinib besylate. He achieved complete remission after induction chemotherapy and remained in remission. His cytogenetics also reverted to normal after consolidation chemotherapy. He relapsed after 3 months of maintenance imatinib besylate.

PMID: 28666495 [PubMed - indexed for MEDLINE]

Update on rare epithelial ovarian cancers: based on the Rare Ovarian Tumors Young Investigator Conference.

J Gynecol Oncol. 2017 Jul;28(4):e54

Authors: Jang JYA, Yanaihara N, Pujade-Lauraine E, Mikami Y, Oda K, Bookman M, Ledermann J, Shimada M, Kiyokawa T, Kim BG, Matsumura N, Kaku T, Kuroda T, Nagayoshi Y, Kawabata A, Iida Y, Kim JW, Quinn M, Okamoto A

Abstract
There has been significant progress in the understanding of the pathology and molecular biology of rare ovarian cancers, which has helped both diagnosis and treatment. This paper provides an update on recent advances in the knowledge and treatment of rare ovarian cancers and identifies gaps that need to be addressed by further clinical research. The topics covered include: low-grade serous, mucinous, and clear cell carcinomas of the ovary. Given the molecular heterogeneity and the histopathological rarity of these ovarian cancers, the importance of designing adequately powered trials or finding statistically innovative ways to approach the treatment of these rare tumors has been emphasized. This paper is based on the Rare Ovarian Tumors Conference for Young Investigators which was presented in Tokyo 2015 prior to the 5th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG).

PMID: 28541641 [PubMed - indexed for MEDLINE]

Child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura with severe ADAMTS13 deficiency: a cohort study of the French national registry for thrombotic microangiopathy.

Lancet Haematol. 2016 Nov;3(11):e537-e546

Authors: Joly BS, Stepanian A, Leblanc T, Hajage D, Chambost H, Harambat J, Fouyssac F, Guigonis V, Leverger G, Ulinski T, Kwon T, Loirat C, Coppo P, Veyradier A, French Reference Center for Thrombotic Microangiopathies

Abstract
BACKGROUND: Thrombotic thrombocytopenic purpura is a rare thrombotic microangiopathy, related to a severe ADAMTS13 deficiency (a disintegrin and metalloprotease with thromboSpondin type 1 repeats, member 13; activity <10% of normal). Childhood-onset thrombotic thrombocytopenic purpura is very rare and initially often misdiagnosed, especially when ADAMTS13 deficiency is acquired (ie, not linked to inherited mutations of the ADAMTS13 gene). We aimed to investigate initial presentation, management, and outcome of acquired thrombotic thrombocytopenic purpura in children.
METHODS: Between Jan 1, 2000, and Dec 31, 2015, we studied a cohort of patients with child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura included in the French national registry for thrombotic microangiopathies at presentation and during follow up. The inclusion criteria were: first episode before age 18 years; ADAMTS13 activity less than 10% of normal at presentation; positive anti-ADAMTS13 autoantibodies during an episode, or a recovery of ADAMTS13 activity in remission, or both. ADAMTS13 activity and anti-ADAMTS13 autoantibodies were investigated by a central laboratory, and medical records were extensively reviewed to collect clinical and biological features with a standardised form. This study is registered with ClinicalTrials.gov, number NCT00426686.
FINDINGS: We enrolled 973 patients with childhood-onset thrombotic microangiopathy, of whom 74 had a severe ADAMTS13 deficiency (activity <10%) at presentation. 24 patients had an inherited thrombotic thrombocytopenic purpura also known as Upshaw-Schulman syndrome and five did not have follow-up data available, thus 45 children had acquired thrombotic thrombocytopenic purpura and were included in our database at presentation. 25 (56%) patients had idiopathic disease and 20 (44%) had miscellaneous associated clinical conditions. At diagnosis, median age was 13 years (IQR 7-16, range 4 months-17 years), with a sex ratio of 2·5 girls to 1 boy. Anti-ADAMTS13 autoantibodies were positive in 37 (82%) of 45 patients (24 [96%] of 25 idiopathic cases and 13 [65%] of 20 non-idiopathic cases). 39 (87%) of 45 patients were given plasma therapy and 21 (47%) received additional rituximab. Four (9%) children died after the first thrombotic thrombocytopenic purpura episode. Long-term follow up of the 41 survivors showed that ten (24%) patients relapsed and systemic lupus erythematosus occurred in two (5%) patients. Preemptive rituximab was used in seven (17%) of 41 patients with acquired thrombotic thrombocytopenic purpura.
INTERPRETATION: Our study shows that child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura have specific clinical, biological and therapeutic features. Long-term follow-up is crucial to prevent relapses of the disease, to identify the occurrence of autoimmune disorders, and to evaluate consequences on social life. Child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura is a crucial diagnosis in the field of paediatric haematologic cytopenias because it is a life-threatening disease requiring a specific management.
FUNDING: Assistance Publique-Hôpitaux de Paris, France.

PMID: 27720178 [PubMed - indexed for MEDLINE]

Chondroid Syringoma.

Foot Ankle Spec. 2017 Apr;10(2):167-169

Authors: Sundling RA, So E, Logan DB

Abstract
Chondroid syringoma is a cutaneous sweat gland tumor. Despite its relative rarity, a benign and malignant variant have been described. We present a case report of chondroid syringoma of the foot in a healthy patient. Definitive diagnosis required histopathologic examination, while treatment included wide resection. Surgeons who are presented with a painless, solid nodule in the lower extremities should be cognizant of this neoplasm.
LEVELS OF EVIDENCE: Therapeutic, Level IV: Case report.

PMID: 27587378 [PubMed - indexed for MEDLINE]

Isolated limb perfusion as a treatment option for rare types of tumours.

Int J Hyperthermia. 2016 Sep;32(6):595-9

Authors: Belgrano V, Ben-Shabat I, Bergh P, Olofsson Bagge R

Abstract
BACKGROUND: Isolated limb perfusion (ILP) is an established and effective treatment for advanced melanoma and soft tissue sarcomas of the extremities with a high overall response rate. The aim of this study was to describe our experience of ILP for more rare types of tumours.
METHODS: Patients with Merkel cell carcinoma (MCC) (n = 4), squamous cell carcinoma (SCC) (n = 2), B-cell lymphoma (n = 1), desmoid tumours (n = 3), pigmented villonodular synovitis (PVNS) (n = 1) and giant cell tumour (n = 1) were treated with ILP and analysed retrospectively.
RESULTS: The four patients with in-transit MCC had three complete responses (CR) and one partial response (PR); the two patients with SCC had one CR and one stable disease (SD); the patients with desmoid tumours had two PR and one SD. A CR was also observed for the patient with a giant cell tumour, but the patient with PVNS had a SD. The patient with cutaneous metastases of B-cell lymphoma showed a CR, however with rapid systemic progression. Local toxicity according to Wieberdink was grade II in 10 patients (83%) and grade III in two patients (17%).
CONCLUSIONS: These results show that ILP can be used as a treatment option also for more rare disease entities when other treatments have failed.

PMID: 27269515 [PubMed - indexed for MEDLINE]

Anaplastic thyroid carcinoma: review of treatment protocols.

Endocr Relat Cancer. 2018 Jan 02;:

Authors: Tiedje V, Stuschke M, Weber F, Dralle H, Moss L, Führer D

Abstract
Anaplastic thyroid carcinoma (ATC) is an orphan disease and in most patients fatal. So far no established treatment is available that prolongs survival. Several large retrospective studies have identified negative prognostic markers, analyzed efficacy of multimodal approaches such as radiotherapy with and without concurrent chemotherapy and chemotherapy protocols. Recently, single case reports have suggested some effectiveness of newer therapies targeting single somatic alterations in ATC. All in all, the conclusions that can be drawn from published retrospective studies and the scarce prospective approaches is that new treatment protocols should be developed including surgery, radiotherapy, chemotherapy and targeted therapy approaches and combinational therapy with immunotherapies. These protocols then need to be evaluated prospectively to improve ATC patients' outcome in routine care.

PMID: 29295821 [PubMed - as supplied by publisher]

Intra-venous bevacizumab in hereditary hemorrhagic telangiectasia (HHT): A retrospective study of 46 patients.

PLoS One. 2017;12(11):e0188943

Authors: Guilhem A, Fargeton AE, Simon AC, Duffau P, Harle JR, Lavigne C, Carette MF, Bletry O, Kaminsky P, Leguy V, Lerolle N, Roux D, Lambert M, Chinet T, Bonnet D, Dupuis-Girod S, Rivière S

Abstract
BACKGROUND: Bevacizumab, an anti-VEGF monoclonal antibody, has recently emerged as a new option for severe forms of hereditary hemorrhagic telangiectasia (HHT). Its utilization in this orphan disease has rapidly spread despite the lack of randomized trials and international guidelines. The objective of this study is to report the main clinical data (baseline characteristics, dose schedule, efficacy, adverse events and deaths) of HHT patients treated by intravenous bevacizumab in France.
METHODS: Retrospective observational study of HHT patients treated with bevacizumab for a severe form of the disease in the 14 centers of the French HHT network.
RESULTS: Forty-six patients (median age: 68 years) were treated between March 2009 and May 2015. Ten patients were treated for high output cardiac failure, 20 patients for severe hemorrhages and 16 for both indications. The standard protocol (6 infusions of 5mg/kg every 2 weeks) was initially used in 89% of the cases but diverse strategies were subsequently applied. A clinical improvement was noted by the referent physician for 74% of the patients with a median effect's duration of 6 months. Wound healing complications led to 2 amputations. Arthralgia/arthritis and arterial hypertension occurred in 5 patients each. One third of the patients were dead at the time of the final update, coherently with age and the poor prognosis of these highly symptomatic patients.
CONCLUSION: Intravenous bevacizumab seems to provide a clinical benefice in severe HHT patients. Precautions concerning wound healing and vascular pathologies must be respected. Prospective double blinded versus placebo trials are needed.

PMID: 29190827 [PubMed - indexed for MEDLINE]

Whole-exome sequencing identifies an α-globin cluster triplication resulting in increased clinical severity of β-thalassemia.

Cold Spring Harb Mol Case Stud. 2017 Nov;3(6):

Authors: Steinberg-Shemer O, Ulirsch JC, Noy-Lotan S, Krasnov T, Attias D, Dgany O, Laor R, Sankaran VG, Tamary H

Abstract
Whole-exome sequencing (WES) has been increasingly useful for the diagnosis of patients with rare causes of anemia, particularly when there is an atypical clinical presentation or targeted genotyping approaches are inconclusive. Here, we describe a 20-yr-old man with a lifelong moderate-to-severe anemia with accompanying splenomegaly who lacked a definitive diagnosis. After a thorough clinical workup and targeted genetic sequencing, we identified a paternally inherited β-globin mutation (HBB:c.93-21G>A, IVS-I-110:G>A), a known cause of β-thalassemia minor. As this mutation alone was inconsistent with the severity of the anemia, we performed WES. Although we could not identify any relevant pathogenic single-nucleotide variants (SNVs) or small indels, copy-number variant (CNV) analyses revealed a likely triplication of the entire α-globin cluster, which was subsequently confirmed by multiplex ligation-dependent probe amplification. Treatment and follow-up was redefined according to the diagnosis of β-thalassemia intermedia resulting from a single β-thalassemia mutation in combination with an α-globin cluster triplication. Thus, we describe a case where the typical WES-based analysis of SNVs and small indels was unrevealing, but WES-based CNV analysis resulted in a definitive diagnosis that informed clinical decision-making. More generally, this case illustrates the value of performing CNV analysis when WES is otherwise unable to elucidate a clear genetic diagnosis.

PMID: 28667000 [PubMed - indexed for MEDLINE]

"Disjointed" approach to rare diseases is still failing patients, warn MPs.

BMJ. 2017 02 27;356:j1037

Authors: O'Dowd A

PMID: 28242776 [PubMed - indexed for MEDLINE]

RE: Afferent Loop Syndrome: A Rare Clinical Condition Diagnosed with Magnetic Resonance Cholangiopancreatography.

Korean J Radiol. 2016 May-Jun;17(3):443

Authors: Aribal S, Kara K, Sönmez G

PMID: 27134532 [PubMed - indexed for MEDLINE]