A Case of Birt-Hogg-Dube Syndrome.

S D Med. 2020 Apr;73(4):168-170

Authors: Jansen C, Nelson J

Abstract
Birt-Hogg-Dube (BHD) syndrome is a rare condition that typically presents with a triad of benign cutaneous papules including fibrofolliculomas, pulmonary cysts and pneumothoraxes, and renal tumors. Though a rare disease, it is an important diagnosis so that monitoring for a renal neoplasm can begin. In this case report we discuss an asymptomatic patient diagnosed with BHD after undergoing a routine skin exam and highlight the importance of diagnosis so that routine screening can be implemented.

PMID: 32445304 [PubMed - indexed for MEDLINE]

Left Aorto-Ventricular Tunnel: A Very Rare Pathology in Adults.

Circ Cardiovasc Imaging. 2020 02;13(2):e009777

Authors: García-Saldivia M, Jiménez-Santos M, Zamorano-Velazquez NF, Riera-Kinkel C, Martínez-Sánchez A, Necoechea-Osuna Y, Moreno-Ruiz L

PMID: 32000511 [PubMed - indexed for MEDLINE]

The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders.

Clin Genet. 2019 08;96(2):140-150

Authors: Jiao Q, Sun H, Zhang H, Wang R, Li S, Sun D, Yang XA, Jin Y

Abstract
This retrospective study aims to investigate the diagnostic yields of multiple strategies of next-generation sequencing (NGS) for children with rare neurological disorders (NDs). A total of 220 pediatric patients with NDs who visited our hospital between Jan 2017 and Dec 2018 and had undergone NGS were included. Most patients were 5 years old or younger, and the number of patients visiting the hospital decreased with age. Seizures were the most common symptom in this cohort. The positive rates for targeted NGS panels (Panel), whole-exome sequencing (WES), and copy number variation sequencing (CNVseq) were 26.5% (9/34), 36.6% (63/172), and 16.7% (22/132), respectively. The positive rate for patients undergoing a combination of WES and CNVseq (WES + CNVseq) was 47.8% (54/113), which was significantly better than the positive rate for patients who underwent WES alone (32.7%, 37/113). A total of 83 variants were found in 42 genes, and SCN1A was the most frequently mutanted gene. Twenty-four CNVs were identified in 22 patients: two CNVs were inherited from the mother; 12 CNVs were de novo; and the CNV origins could not be determined in 10 patients. WES + CNVseq may potentially be the mostly effective NGS approach for diagnosis of rare NDs in pediatric patients.

PMID: 30945278 [PubMed - indexed for MEDLINE]

Reconsidering Genetic Testing for Neonatal Polycystic Kidney Disease.

Kidney Int Rep. 2020 Aug;5(8):1316-1319

Authors: VanNoy GE, Wojcik MH, Genetti CA, Mullen TE, Agrawal PB, Stein DR

PMID: 32775833 [PubMed - as supplied by publisher]

Wilson's Disease: Diagnosis of Wilson's Disease in Ethiopian Young Sisters.

Case Rep Med. 2020;2020:7650170

Authors: Bekele N, Ewnetu F, Hailu T, Tegegne Z, Tadesse A

Abstract
Background: Wilson's disease is an inherited autosomal recessive disorder of copper metabolism. Clinical signs, biochemical parameters, histologic findings, and/or ATP7B genetic testing are required to diagnose Wilson's disease. Case Presentation. 25-year-old and 22-year-old young women (siblings) presented to the University of Gondar Hospital, Northwest Ethiopia, with difficulty of keeping balance of 3-year duration and progressive extremity weakness of 5-year duration, respectively. Both siblings had visible ocular Kayser-Fleischer rings, low serum ceruloplasmin level and increased urinary copper content, ultrasound-evidenced cirrhotic liver disease, and axial T2-weighted MRI hyperintensities in basal ganglia, thalamus, and brainstem (midbrain and pons). Diagnosis of Wilson's disease was established in both patients using a diagnostic scoring system proposed by "8th International Meeting on Wilson Disease and Menkes Disease, Leipzig (2001)." Treatment with D-penicillamine as a chelator and zinc sulphate as a metalothionein-inductor was started. Screening of their family members was recommended.
Conclusion: Wilson's disease, declared to be an orphan disease, requires clinical acumen of physicians and expensive investigation modalities for prompt recognition and is inaccessible as required, lifelong drugs for treatment.

PMID: 32774387 [PubMed - as supplied by publisher]

Familial and genetic factors in laryngeal cleft: Have we learned anything?

Int J Pediatr Otorhinolaryngol. 2020 Jul 29;138:110283

Authors: Dombrowski ND, Li Y, Zhao CX, Agrawal PB, Rahbar R

Abstract
INTRODUCTION: Laryngeal clefts are rare congenital anomalies characterized by failed fusion of the posterior cricoid lamina or incomplete development of the tracheoesophageal septum. While most cases are sporadic, laryngeal cleft may be associated with other congenital anomalies or syndromes. Though not frequently reported, familial occurrence of laryngeal cleft has been noted in our clinical experience. The goal of this research is to describe the existing literature and our own experience surrounding familial occurrence of laryngeal cleft that may help elucidate its underlying genetic basis.
METHODS: Comprehensive literature search was conducted and retrospective chart review was performed on 8 sets of siblings diagnosed at our institution. Data assessed included demographics, type of cleft, and genetic findings.
RESULTS: Laryngeal cleft appears to be mostly sporadic. We evaluated data at our institution over a 10-year period and identified 19 patients from 8 families demonstrating familial occurrence of laryngeal cleft. Six (75%) families had two affected siblings, one family (12.5%) had three affected siblings, and one family (12.5%) had four affected siblings. There was no evidence of sex predilection, with half the patients being male (10/19, 52.6%). Fourteen patients (73.7%) had Type 1 clefts and five (26.3%) had Type 2 clefts. Genetic findings were available for review in five patients from three families.
CONCLUSION: Beyond a few known syndromes, laryngeal cleft has largely been thought to be sporadic. However, findings from the existing literature and our own experience with familial laryngeal cleft in eight families suggest additional genetic factors are yet to be elucidated.

PMID: 32771712 [PubMed - as supplied by publisher]

Courtesy Stigma and Social Support: An Exploration of Fathers' Buffering Strategies and Blocking Rationalizations.

Health Commun. 2019 11;34(13):1543-1554

Authors: Tikkanen SA, Peterson BL, Parsloe SM

Abstract
This study extends scholarship on stigma management communication and social support by exploring the experiences of fathers of children living with a rare health condition, Sturge-Weber Syndrome. Findings from this interview-based interpretive study reveal that fathers assuaged the negative effects of stigma on their children-and courtesy stigma on themselves-by employing buffering strategies, including reactive and preemptive information sharing, preparatory conversations, and support blocking. Further, fathers offered three rationalizations for their blocking behaviors-reasoning that to accept support would violate social norms, as well as privacy expectations and that accepting support was not worth the effort (social exchange). These findings encourage scholars to continue to upend predominant constructions of masculinity and also call to question prevailing assumptions about the relationship between technology and privacy.

PMID: 30067393 [PubMed - indexed for MEDLINE]

Drug Therapies for the Management of Sickle Cell Disease.

F1000Res. 2020;9:

Authors: Rai P, Ataga KI

Abstract
Sickle cell disease (SCD) afflicts millions of people worldwide but is referred to as an orphan disease in the United States. Over the past several decades, there has been an increasing understanding of the pathophysiology of SCD and its complications. While most individuals with SCD in resource-rich countries survive into adulthood, the life expectancy of patients with SCD remains substantially shorter than for the general African-American population. SCD can be cured using hematopoietic stem cell transplantation and possibly gene therapy, but these treatment approaches are not available to most patients, the majority of whom reside in low- and middle-income countries. Until relatively recently, only one drug, hydroxyurea, was approved by the US Food and Drug Administration to ameliorate disease severity. Multiple other drugs (L-glutamine, crizanlizumab, and voxelotor) have recently been approved for the treatment of SCD, with several others at various stages of clinical testing. The availability of multiple agents to treat SCD raises questions related to the choice of appropriate drug therapy, combination of multiple agents, and affordability of recently approved products. The enthusiasm for new drug development provides opportunities to involve patients in low- and middle-income nations in the testing of potentially disease-modifying therapies and has the potential to contribute to capacity building in these environments. Demonstration that these agents, alone or in combination, can prevent or decrease end-organ damage would provide additional evidence for the role of drug therapies in improving outcomes in SCD.

PMID: 32765834 [PubMed - as supplied by publisher]

Loss of Tmem106b exacerbates FTLD pathologies and causes motor deficits in progranulin-deficient mice.

EMBO Rep. 2020 Aug 05;:e50197

Authors: Zhou X, Brooks M, Jiang P, Koga S, Zuberi AR, Baker MC, Parsons TM, Castanedes-Casey M, Phillips V, Librero AL, Kurti A, Fryer JD, Bu G, Lutz C, Dickson DW, Rademakers R

Abstract
Progranulin (PGRN) and transmembrane protein 106B (TMEM106B) are important lysosomal proteins implicated in frontotemporal lobar degeneration (FTLD) and other neurodegenerative disorders. Loss-of-function mutations in progranulin (GRN) are a common cause of FTLD, while TMEM106B variants have been shown to act as disease modifiers in FTLD. Overexpression of TMEM106B leads to lysosomal dysfunction, while loss of Tmem106b ameliorates lysosomal and FTLD-related pathologies in young Grn-/- mice, suggesting that lowering TMEM106B might be an attractive strategy for therapeutic treatment of FTLD-GRN. Here, we generate and characterize older Tmem106b-/- Grn-/- double knockout mice, which unexpectedly show severe motor deficits and spinal cord motor neuron and myelin loss, leading to paralysis and premature death at 11-12 months. Compared to Grn-/- , Tmem106b-/- Grn-/- mice have exacerbated FTLD-related pathologies, including microgliosis, astrogliosis, ubiquitin, and phospho-Tdp43 inclusions, as well as worsening of lysosomal and autophagic deficits. Our findings confirm a functional interaction between Tmem106b and Pgrn and underscore the need to rethink whether modulating TMEM106B levels is a viable therapeutic strategy.

PMID: 32761777 [PubMed - as supplied by publisher]

Rare Human Diseases: Model Organisms in Deciphering the Molecular Basis of Primary Ciliary Dyskinesia.

Cells. 2019 12 11;8(12):

Authors: Poprzeczko M, Bicka M, Farahat H, Bazan R, Osinka A, Fabczak H, Joachimiak E, Wloga D

Abstract
Primary ciliary dyskinesia (PCD) is a recessive heterogeneous disorder of motile cilia, affecting one per 15,000-30,000 individuals; however, the frequency of this disorder is likely underestimated. Even though more than 40 genes are currently associated with PCD, in the case of approximately 30% of patients, the genetic cause of the manifested PCD symptoms remains unknown. Because motile cilia are highly evolutionarily conserved organelles at both the proteomic and ultrastructural levels, analyses in the unicellular and multicellular model organisms can help not only to identify new proteins essential for cilia motility (and thus identify new putative PCD-causative genes), but also to elucidate the function of the proteins encoded by known PCD-causative genes. Consequently, studies involving model organisms can help us to understand the molecular mechanism(s) behind the phenotypic changes observed in the motile cilia of PCD affected patients. Here, we summarize the current state of the art in the genetics and biology of PCD and emphasize the impact of the studies conducted using model organisms on existing knowledge.

PMID: 31835861 [PubMed - indexed for MEDLINE]

[Rare occupational diseases].

Internist (Berl). 2020 Jun;61(6):626-633

Authors: Drexler H

Abstract
Rare work-related illnesses do not usually meet the requirements to be recognised and compensated as a legal occupational disease. However, common diseases (e.g. ovarian carcinoma) are sometimes caused by occupational influences (e.g. asbestos), making the occupational disease ovarian cancer caused by occupational exposure to asbestos a rare disease. Since in our modern working world the occupational influences that are harmful to health are decreasing qualitatively (substitutes) and quantitatively (limit values), the diseases they cause are also becoming increasingly rare.

PMID: 32328688 [PubMed - indexed for MEDLINE]

Which is Better for Patients with Breast Cancer: Totally Implanted Vascular Access Devices (TIVAD) or Peripherally Inserted Central Catheter (PICC)?

World J Surg. 2020 03;44(3):1004-1005

Authors: Toro A, Schembari E, Mattone E, Di Carlo I

PMID: 31541273 [PubMed - indexed for MEDLINE]

Imaging Diagnosis of Epithelioid Hemangioendothelioma in Thoracic Vertebrae and Liver.

Ann Thorac Surg. 2020 06;109(6):e407-e410

Authors: Zeng Y, Leng X, Chen P, Luo J, Zhou Z

Abstract
Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor of uncertain biologic behavior. Most cases come out as a single lesion of the soft tissue but also may appear in the lung, liver, and other locations. EHE in bone, especially in thoracic vertebrae, is an extremely rare occurrence and signifies a challenge for the imaging diagnosis. This paper presents a rare case of EHE occurring in thoracic vertebrae and liver revealed by fluoride-18-fluorodeoxyglucose-positron emission tomography and magnetic resonance imaging to provide a better understanding of its clinical application and further insight into diagnosing a rare thoracic tumor.

PMID: 31794741 [PubMed - indexed for MEDLINE]

Bronchoscopic Surgery for a Solitary Tracheal Tumor of Tracheobronchopathia Osteochondroplastica.

Ann Thorac Surg. 2020 06;109(6):e419-e421

Authors: Sakaguchi Y, Matsumoto K, Nishioka K, Iizuka N, Hirayama Y, Kitaoka A, Tanimura K, Takahashi KI, Kato M

Abstract
Tracheobronchopathia osteochondroplastica is a rare benign condition in which multiple cartilaginous or bony submucosal nodules project into the trachea or bronchi. A 71-year-old man complained of cough for 3 months. Computed tomography scanning revealed a calcified tracheal tumor near the tracheal bifurcation. Pulmonary function testing indicated airflow limitation, and bronchoscopic examination confirmed a solitary rigid tumor. Bronchoscopic resection was performed under general anesthesia, and the tumor was detached by cauterizing its stem with high-frequency coagulation. The tumor was pathologically indicative of tracheobronchopathia osteochondroplastica. After surgery, the clinical signs of cough and dyspnea resolved and pulmonary function normalized.

PMID: 31606516 [PubMed - indexed for MEDLINE]

Epidemiology of achondroplasia: A population-based study in Europe.

Am J Med Genet A. 2019 09;179(9):1791-1798

Authors: Coi A, Santoro M, Garne E, Pierini A, Addor MC, Alessandri JL, Bergman JEH, Bianchi F, Boban L, Braz P, Cavero-Carbonell C, Gatt M, Haeusler M, Klungsøyr K, Kurinczuk JJ, Lanzoni M, Lelong N, Luyt K, Mokoroa O, Mullaney C, Nelen V, Neville AJ, O'Mahony MT, Perthus I, Rankin J, Rissmann A, Rouget F, Schaub B, Tucker D, Wellesley D, Wisniewska K, Zymak-Zakutnia N, Barišić I

Abstract
Achondroplasia is a rare genetic disorder resulting in short-limb skeletal dysplasia. We present the largest European population-based epidemiological study to date using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network. All cases of achondroplasia notified to 28 EUROCAT registries (1991-2015) were included in the study. Prevalence, birth outcomes, prenatal diagnosis, associated anomalies, and the impact of paternal and maternal age on de novo achondroplasia were presented. The study population consisted of 434 achondroplasia cases with a prevalence of 3.72 per 100,000 births (95%CIs: 3.14-4.39). There were 350 live births, 82 terminations of pregnancy after prenatal diagnosis, and two fetal deaths. The prenatal detection rate was significantly higher in recent years (71% in 2011-2015 vs. 36% in 1991-1995). Major associated congenital anomalies were present in 10% of cases. About 20% of cases were familial. After adjusting for maternal age, fathers >34 years had a significantly higher risk of having infants with de novo achondroplasia than younger fathers. Prevalence was stable over time, but regional differences were observed. All pregnancy outcomes were included in the prevalence estimate with 80.6% being live born. The study confirmed the increased risk for older fathers of having infants with de novo achondroplasia.

PMID: 31294928 [PubMed - indexed for MEDLINE]

Anal adenocarcinoma: Treatment outcomes and trends in a rare disease entity.

Cancer Med. 2019 07;8(8):3855-3863

Authors: Wegner RE, White RJ, Hasan S, Raj M, Monga D, Finley G, Kirichenko AV, McCormick J

Abstract
IMPORTANCE: Primary Adenocarcinoma of the anus is a rare disease with a poor prognosis and thus tends to have a more aggressive treatment algorithm, typically involving a surgical approach. Prior to 2001, a few retrospective studies outlined improved outcomes with the incorporation of surgery with chemoradiation. However, since the publication of these studies, advancement in radiotherapy modalities and imaging have left the question of improved outcomes while reserving surgery for salvage.
OBJECTIVE: We conducted this National Cancer Database (NCDB)-driven retrospective study to analyze treatment trends and outcomes in the current time from 2004 to 2015 with respect to chemoradiation and surgery.
DESIGN: Retrospective NCDB tumor registry data review-using propensity score-adjusted multivariable analyses for survival.
SETTING: Database review.
PARTICIPANTS: We selected for patients listed in the NCDB with AJCC stage 1-3 anal adenocarcinoma diagnosed between 2004 and 2015 and selected out patients with undocumented/stage 4 disease, those with radiation outside the pelvis, not treated with systemic therapy and patients lost to follow-up.
EXPOSURE(S): None.
MAIN OUTCOMES AND MEASURES: Overall survival and use of surgery in the up-front management of anal adenocarcinoma.
RESULTS: Of the 1729 patients eligible in this study, 1028 were treated with surgery as up-front management and 701 had definitive chemoradiation. Median overall survival for all patients was 55 months with a 5-year survival rate of 55%. Patients treated without surgery had worse overall survival, median survival of 45 months compared to 87 months (P < 0.0001) with 5-year survival rates of 42% and 55% in favor of incorporation of surgery. Analysis across patients treated with surgery alone, surgery followed by adjuvant chemoradiation, neoadjuvant chemoradiation followed by surgery, and chemoradiation alone had median survival rates of 78, 83, 92, and 46 months, respectively. Propensity score-adjusted multivariable analysis identified older age, grade 3, high comorbidity score, and lack of surgery as predictive of worse outcome.
CONCLUSIONS AND RELEVANCE: The results of the NCDB analysis indicate improved overall survival with the incorporation of surgery into the initial management of anal adenocarcinoma when compared to chemoradiation alone, despite the omission of surgery in up to 50% of the cases logged. Our results corroborate earlier studies published prior to the year 2000 for surgery to be included in the definitive management of anal adenocarcinoma.

PMID: 31173487 [PubMed - indexed for MEDLINE]

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Case 278: Mutation in ROBO3 Gene-Horizontal Gaze Palsy and Progressive Scoliosis.

Radiology. 2020 06;295(3):736-740

Authors: Scortegagna FA, Pacheco FT, Nunes RH, Serpa A, Migliavacca MP, da Rocha AJ

Abstract
HistoryA 13-year-old girl was born to consanguineous parents. She presented with mild intellectual impairment, convergent strabismus, horizontal gaze palsy, and bilateral abducens palsy. Vertical gaze was preserved, and no abnormalities suggesting facial paralysis were noted. In addition, she reported progressive back pain since she was 5 years old. Other symptoms were denied. No medications or related drugs had been administered thus far. The patient underwent brain MRI for further evaluation. Current and previous spine radiographs were also reviewed.

PMID: 32421468 [PubMed - indexed for MEDLINE]

Artificial Intelligence System Approaching Neuroradiologist-level Differential Diagnosis Accuracy at Brain MRI.

Radiology. 2020 06;295(3):626-637

Authors: Rauschecker AM, Rudie JD, Xie L, Wang J, Duong MT, Botzolakis EJ, Kovalovich AM, Egan J, Cook TC, Bryan RN, Nasrallah IM, Mohan S, Gee JC

Abstract
Background Although artificial intelligence (AI) shows promise across many aspects of radiology, the use of AI to create differential diagnoses for rare and common diseases at brain MRI has not been demonstrated. Purpose To evaluate an AI system for generation of differential diagnoses at brain MRI compared with radiologists. Materials and Methods This retrospective study tested performance of an AI system for probabilistic diagnosis in patients with 19 common and rare diagnoses at brain MRI acquired between January 2008 and January 2018. The AI system combines data-driven and domain-expertise methodologies, including deep learning and Bayesian networks. First, lesions were detected by using deep learning. Then, 18 quantitative imaging features were extracted by using atlas-based coregistration and segmentation. Third, these image features were combined with five clinical features by using Bayesian inference to develop probability-ranked differential diagnoses. Quantitative feature extraction algorithms and conditional probabilities were fine-tuned on a training set of 86 patients (mean age, 49 years ± 16 [standard deviation]; 53 women). Accuracy was compared with radiology residents, general radiologists, neuroradiology fellows, and academic neuroradiologists by using accuracy of top one, top two, and top three differential diagnoses in 92 independent test set patients (mean age, 47 years ± 18; 52 women). Results For accuracy of top three differential diagnoses, the AI system (91% correct) performed similarly to academic neuroradiologists (86% correct; P = .20), and better than radiology residents (56%; P < .001), general radiologists (57%; P < .001), and neuroradiology fellows (77%; P = .003). The performance of the AI system was not affected by disease prevalence (93% accuracy for common vs 85% for rare diseases; P = .26). Radiologists were more accurate at diagnosing common versus rare diagnoses (78% vs 47% across all radiologists; P < .001). Conclusion An artificial intelligence system for brain MRI approached overall top one, top two, and top three differential diagnoses accuracy of neuroradiologists and exceeded that of less-specialized radiologists. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Zaharchuk in this issue.

PMID: 32255417 [PubMed - indexed for MEDLINE]

Protecting the rare during a rare pandemic.

Med J Aust. 2020 07;213(2):94-94.e1

Authors: Baynam GS, Wicking C, Bhattacharya K, Millis N

PMID: 32570278 [PubMed - indexed for MEDLINE]