The need for a next-generation public health response to rare diseases.

Genet Med. 2016 10 27;19(5):489-490

Authors: Valdez R, Grosse SD, Khoury MJ

PMID: 27787501 [PubMed - indexed for MEDLINE]

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/05/01

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Atypical presentations associated with non-polyalanine repeat PHOX2B mutations.

Am J Med Genet A. 2018 Apr 28;:

Authors: Katwa U, D'Gama AM, Qualls AE, Donovan LM, Heffernan J, Shi J, Agrawal PB

Abstract
Congenital central hypoventilation syndrome (CCHS) is a disorder of ventilatory control and autonomic dysregulation that can be caused by mutations in the paired-like homeobox 2B (PHOX2B) gene. The majority of CCHS cases are caused by polyalanine repeat mutations (PARMs) in PHOX2B; however, in rare cases, non-polyalanine repeat mutations (NPARMs) have been identified. Here, we report two patients with NPARMs in PHOX2B. Patient 1 has a mild CCHS phenotype seen only on polysomnogram, which was performed for desaturations and stridor following a bronchiolitis episode, and characterized by night-time hypoventilation and a history of ganglioneuroblastoma. She carried a novel de novo missense variant, p.R102S (c.304C > A), in exon 2. Patient 2 has an atypical CCHS phenotype including micrognathia, gastroesophageal reflux, stridor, hypopnea, and intermittent desaturations. Sleep study demonstrated that Patient 2 had daytime and night-time hypercarbia with obstructive sleep apnea, requiring tracheostomy. On PHOX2B sequencing, she carried a recently identified nonsense variant, p.Y78* (c.234C > G), in exon 1. In summary, we present two patients with CCHS and identified NPARMs in PHOX2B who have distinct differences in phenotype severity, further elucidating the range of clinical outcomes in CCHS and illustrating the necessity of considering PHOX2B mutations when encountering atypical CCHS presentations.

PMID: 29704303 [PubMed - as supplied by publisher]

Orphan disease: Cherubism, optic atrophy, and short stature.

Indian J Radiol Imaging. 2018 Jan-Mar;28(1):111-114

Authors: Jeevanandham B, Ramachandran R, Dhanapal V, Subramanian I, Sai V

Abstract
A 12-year-old female presented with complaints of progressive visual impairment in both her eyes. On clinical examination, she was short for her age and her ophthalmoscopic examination revealed bilateral optic atrophy. Computed tomography of the patient revealed multiple expansile lytic lesions of mandible suggesting cherubism. The optic atrophy was confirmed on magnetic resonance imaging, which additionally revealed bilateral retrocerebellar arachnoid cysts. This association of cherubism with optic atrophy and short stature was grouped as orphan disease by National Institutes of Health and only one case was reported in the literature so far.

PMID: 29692538 [PubMed]

[Neuroendocrine tumors of the breast: Myth or reality? A systematic review].

Bull Cancer. 2018 Apr;105(4):431-439

Authors: Cheymol C, Abramovici O, Do Cao C, Dumont A, Robin YM, El Hajbi F, Dansin E, Bonneterre J, Lauridant G

Abstract
Primary neuroendocrine breast carcinomas are rare and little-known tumors. Only a limited number of studies on neuroendocrine breast carcinomas have been reported in the literature, and the vast majority of them are small retrospective series or case reports. According to the World Health Organization (WHO), they account for only 2 % to 5 % of breast cancers. Their diagnosis relies on the presence of a neuroendocrine architecture and the expression of neuroendocrine markers (chromogranin A and/or synaptophysin). The revised 2012 WHO classification subdivides them into three categories: (i) well-differentiated neuroendocrine carcinomas, (ii) poorly differentiated neuroendocrine carcinomas or small-cell carcinomas, and (iii) invasive breast carcinomas with neuroendocrine differentiation. Their clinical features and radiological characteristics are not different from those of other types of breast cancer. Because of discordant results, their clinical outcome is still poorly defined. So far, no standard treatment has been established, and most clinicians draw on their experience of invasive ductal cancer. The role of specific treatments like platinum-based chemotherapy, somatostatin analogues, peptide receptor radionucleide therapy or temozolomide remains unclear. A better knowledge of the molecular pathways involved in their carcinogenesis could help to identify new potential therapeutic targets. The efficacy of targeted therapies has to be studied.

PMID: 29567279 [PubMed - indexed for MEDLINE]

Novel founder intronic variant in SLC39A14 in two families causing Manganism and potential treatment strategies.

Mol Genet Metab. 2018 Apr 06;:

Authors: Rodan LH, Hauptman M, D'Gama AM, Qualls AE, Cao S, Tuschl K, Al-Jasmi F, Hertecant J, Hayflick SJ, Wessling-Resnick M, Yang ET, Berry GT, Gropman A, Woolf AD, Agrawal PB

Abstract
Congenital disorders of manganese metabolism are rare occurrences in children, and medical management of these disorders is complex and challenging. Homozygous exonic mutations in the manganese transporter SLC39A14 have recently been associated with a pediatric-onset neurodegenerative disorder characterized by brain manganese accumulation and clinical signs of manganese neurotoxicity, including parkinsonism-dystonia. We performed whole exome sequencing on DNA samples from two unrelated female children from the United Arab Emirates with progressive movement disorder and brain mineralization, identified a novel homozygous intronic mutation in SLC39A14 in both children, and demonstrated that the mutation leads to aberrant splicing. Both children had consistently elevated serum manganese levels and were diagnosed with SLC39A14-associated manganism. Over a four-year period, we utilized a multidisciplinary management approach for Patient 1 combining decreased manganese dietary intake and chelation with symptomatic management of dystonia. Our treatment strategy appeared to slow disease progression, but did not lead to a cure or reversal of already established deficits. Clinicians should consider testing for noncoding mutations in the diagnosis of congenital disorders of manganese metabolism and utilizing multidisciplinary approaches in the management of these disorders.

PMID: 29685658 [PubMed - as supplied by publisher]

The Spectrum of Caregiving in Palliative Care for Serious, Advanced, Rare Diseases: Key Issues and Research Directions.

J Palliat Med. 2016 Jul;19(7):698-705

Authors: Adams LS, Miller JL, Grady PA

Abstract
Rare diseases are often life-limiting conditions, the majority of which require constant caregiving needs. The realization of a spectrum of palliative care throughout the trajectory of rare diseases could ensure individualized and caregiver-focused approaches to the care of patients and families. In June 2015, the National Institute of Nursing Research (NINR), the lead institute at the National Institutes of Health for end-of-life research, in conjunction with the National Center for Advancing Translational Sciences, Office of Rare Diseases Research (ORDR) held an interdisciplinary workshop on the unique challenges of caregiving and palliative care in adult and pediatric rare diseases. The panel identified gaps in current knowledge, and afforded suggestions for research opportunities in palliative care science to improve the care of individuals with serious, advanced, rare diseases and their caregivers. This meeting provided an in-depth opportunity to incorporate new concepts into palliative and end-of-life care for individuals with a range of rare diseases and their caregivers. This report presents a summary of the workshop.

PMID: 27249541 [PubMed - indexed for MEDLINE]

Ecthyma gangrenosum caused by Citrobacter freundii.

BMJ Case Rep. 2017 Jul 27;2017:

Authors: Hawkley T, Chang D, Pollard W, Ferraro D

Abstract
A 55-year-old man undergoing chemotherapy for recurrent multiple myeloma presented with a 2-day history of bilateral lower leg rash with pain and oedema. On examination, there were numerous non-palpable retiform pruritic patches over both lower legs. Skin pnch biopsy demonstrated a diffuse interstitial neutrophilic infiltrate with necrosis. Peripheral blood and skin tissue cultures both isolated Citrobacterfreundii, consistent with a rare form of ecthyma gangrenosum. The patient responded with appropriate antibiotic therapy and removal of medical port. He made a full recovery from this infectious complication of his underlying immunosuppression.

PMID: 28751433 [PubMed - indexed for MEDLINE]

Severe hypokalaemia as a cause of acute transient quadriparesis.

BMJ Case Rep. 2017 Jul 27;2017:

Authors: Lybecker MB, Madsen HB, Bruun JM

Abstract
Hypokalaemic paralysis covers a heterogeneous group of disorders caused either by an enhanced shift of potassium into the cells or following a significant renal or gastrointestinal loss of potassium. We present the case of a 48-year-old Caucasian man with paralysis of both upper and lower extremities. ECG showed sinus rhythm and characteristic changes of hypokalaemia with depression of the ST segment, prolonged QTc interval of 581ms and U waves seen as a small positive deflection at the T wave in the middle precordial leads. We suspected the cause of hypokalaemia leading to paralysis to be due to administration of high doses of furosemide without oral potassium supplementation coupled with regular use of insulin. Initial therapy included both oral and intravenous potassium replacement and close monitoring of cardiac rhythm and serum potassium levels. Twenty-four hours after admission, the potassium level had normalised and the patient slowly recovered and gained strength. The patient was discharged after 1 week of careful follow-up and did not experience any serious degree of rebound hyperkalaemia. At the time of discharge, all laboratory tests were normal and ECG revealed a normal sinus rhythm and normal QTc intervals.

PMID: 28751432 [PubMed - indexed for MEDLINE]

Cryptogenic multifocal ulcerous stenosing enteritis: Radiologic features and clinical behavior.

World J Gastroenterol. 2017 Jul 07;23(25):4615-4623

Authors: Hwang J, Kim JS, Kim AY, Lim JS, Kim SH, Kim MJ, Kim MS, Song KD, Woo JY

Abstract
AIM: To investigate the characteristic radiologic findings of cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) which can be differentiated from other similar bowel disease and to assess their clinical behavior.
METHODS: Twenty pathologically and clinically confirmed CMUSE patients (males:females = 8:12; mean age: 40.4 years) between March 2002 and August 2015 from seven academic centers in South Korea were retrospectively reviewed. We evaluated small bowel series (SBS; n = 25), computed tomography (CT) enterography (n = 21), magnetic resonance (MR) enterography (n = 2), and abdominopelvic CT (n = 18) images, focusing on enteric and perienteric manifestations. Any change in radiologic features during follow-up period was recorded. We evaluated clinical data including presenting symptoms, laboratory finding and presence of relapse from electronic medical records. Histopathologic findings were also evaluated.
RESULTS: The main symptoms were abdominal pain (n = 12) and anemia (n = 10). All patients showed small bowel strictures (n = 52, mean: 2.6 per patient) on initial CT/MR, located in the ileum (n = 47) or jejunum (n = 5). Strictures showed short-length (mean: 10.44 mm) and circumferential bowel wall thickening (mean: 5.56 mm) with layered enhancement (n = 48) that were also noted on initial SBS (n = 36) with shallow ulcers (n = 10). Some ulcerative lesions or wall thickening progressed into strictures on follow-up SBS/CT, and some strictures revealed recurrent ulceration on follow-up SBS. There were no penetrating disease features like fistula or abscess and no gastrointestinal tract involvement except the small bowel. Nine patients experienced disease recurrence (median relapse-free period: 32 mo) even post-operatively. Histopathologic features of surgically resected specimens were characterized as multiple superficial ulcerations confined to mucosa or submucosa and multiple strictures.
CONCLUSION: Under characteristic radiologic findings with multiple short-segmental strictures and/or shallow ulcers of the small intestine, CMUSE should be considered when assessing patients with recurrent abdominal pain and anemia.

PMID: 28740350 [PubMed - indexed for MEDLINE]

[Raising the internist's know-how in the field of rare diseases: mitochondrial diseases as an illustrative example].

Rev Med Suisse. 2017 Jan 18;13(546):159-163

Authors: Tran C, Serratrice J, Nuoffer JM, Schaller A, Favrat B, Barbey F, Lobrinus JA, Kern I, Kuntzer T, Ballhausen D

Abstract
Rare Diseases, defined by a prevalence of less than 1 per 2000 persons, affect 36 million people in Europe, 500 000 in Switzerland, corresponding to 6-8% of the general population. 7000 rare diseases are currently recorded.Mitochondrial diseases are a heterogeneous group of genetic diseases. They are characterized by intracellular failure of energy production and affect predominantly energy-dependent tissues. The clinical presentation is not always suggestive, particularly in adulthood. In order to reach the diagnosis, a prerequisite is to think of them. In this article, we will focus on the clinical aspects of mitochondrial disorders in order to give the internist simple tools on how not to miss those rare diseases in his daily practice.

PMID: 28703515 [PubMed - indexed for MEDLINE]

The FDA Breakthrough-Drug Designation - Four Years of Experience.

N Engl J Med. 2018 04 12;378(15):1444-1453

Authors: Darrow JJ, Avorn J, Kesselheim AS

PMID: 29641970 [PubMed - indexed for MEDLINE]

Affordability Challenges to Value-Based Pricing: Mass Diseases, Orphan Diseases, and Cures.

Value Health. 2018 03;21(3):252-257

Authors: Danzon PM

Abstract
OBJECTIVES: To analyze how value-based pricing (VBP), which grounds the price paid for pharmaceuticals in their value, can manage "affordability" challenges, defined as drugs that meet cost-effectiveness thresholds but are "unaffordable" within the short-run budget.
METHODS: Three specific contexts are examined, drawing on recent experience. First, an effective new treatment for a chronic, progressive disease, such as hepatitis C, creates a budget spike that is transitory because initial prevalence is high, relative to current incidence. Second, "cures" that potentially provide lifetime benefits may claim abnormally high VBP prices, with high immediate budget impact potentially/partially offset by deferred cost savings. Third, although orphan drugs in principle target rare diseases, in aggregate they pose affordability concerns because of the growing number of orphan indications and increasingly high prices.
RESULTS: For mass diseases, the transitory budget impact of treating the accumulated patient stock can be managed by stratified rollout that delays treatment of stable patients and prioritizes patients at high risk of deterioration. Delay spreads the budget impact and permits potential savings from launch of competing treatments. For cures, installment payments contingent on outcomes could align payment flows and appropriately shift risk to producers. This approach, however, entails high administrative and incentive costs, especially if applied across multiple payers in the United States. For orphan drugs, the available evidence on research and development trends and returns argues against the need for a higher VBP threshold to incentivize research and development in orphan drugs, given existing statutory benefits under orphan drug legislation.

PMID: 29566830 [PubMed - indexed for MEDLINE]

Segmental testicular infarction: a case report.

J Med Case Rep. 2017 May 18;11(1):140

Authors: Smets T, Reichman G, Michielsen DPJ

Abstract
BACKGROUND: Segmental testicular infarction is a very rare condition, which can mimic a testicular torsion or testicular cancer. Correct diagnosis is difficult but it is important to avoid unnecessary radical treatment.
CASE PRESENTATION: We report a clinical case of a 36-year-old white man who presented at our emergency department with subacute testicular pain. A urine analysis, Doppler ultrasound, surgical exploration, blood analysis, and magnetic resonance imaging were performed to diagnose his condition, to exclude a testicular torsion, and to raise confidence in its non-malignancy. He was treated conservatively. At follow-up, a few months after the incident, he no longer had complaints. Ultrasonography showed remaining hypo-echogenicity of the left upper pole, indicating a sequel of ischemia.
CONCLUSIONS: Segmental testicular infarction is a rare condition which can be easily confused with a testicular torsion or a testicular tumor. This case report can be helpful in recognizing and diagnosing this condition. Making the right diagnosis is important since it can prevent an unnecessary radical treatment.

PMID: 28514960 [PubMed - indexed for MEDLINE]

Linear models of coregionalization for multivariate lattice data: Order-dependent and order-free cMCARs.

Stat Methods Med Res. 2016 Aug;25(4):1118-44

Authors: MacNab YC

Abstract
This paper concerns with multivariate conditional autoregressive models defined by linear combination of independent or correlated underlying spatial processes. Known as linear models of coregionalization, the method offers a systematic and unified approach for formulating multivariate extensions to a broad range of univariate conditional autoregressive models. The resulting multivariate spatial models represent classes of coregionalized multivariate conditional autoregressive models that enable flexible modelling of multivariate spatial interactions, yielding coregionalization models with symmetric or asymmetric cross-covariances of different spatial variation and smoothness. In the context of multivariate disease mapping, for example, they facilitate borrowing strength both over space and cross variables, allowing for more flexible multivariate spatial smoothing. Specifically, we present a broadened coregionalization framework to include order-dependent, order-free, and order-robust multivariate models; a new class of order-free coregionalized multivariate conditional autoregressives is introduced. We tackle computational challenges and present solutions that are integral for Bayesian analysis of these models. We also discuss two ways of computing deviance information criterion for comparison among competing hierarchical models with or without unidentifiable prior parameters. The models and related methodology are developed in the broad context of modelling multivariate data on spatial lattice and illustrated in the context of multivariate disease mapping. The coregionalization framework and related methods also present a general approach for building spatially structured cross-covariance functions for multivariate geostatistics.

PMID: 27566769 [PubMed - indexed for MEDLINE]

Reconstruction of complex single-cell trajectories using CellRouter.

Nat Commun. 2018 03 01;9(1):892

Authors: Lummertz da Rocha E, Rowe RG, Lundin V, Malleshaiah M, Jha DK, Rambo CR, Li H, North TE, Collins JJ, Daley GQ

Abstract
A better understanding of the cell-fate transitions that occur in complex cellular ecosystems in normal development and disease could inform cell engineering efforts and lead to improved therapies. However, a major challenge is to simultaneously identify new cell states, and their transitions, to elucidate the gene expression dynamics governing cell-type diversification. Here, we present CellRouter, a multifaceted single-cell analysis platform that identifies complex cell-state transition trajectories by using flow networks to explore the subpopulation structure of multi-dimensional, single-cell omics data. We demonstrate its versatility by applying CellRouter to single-cell RNA sequencing data sets to reconstruct cell-state transition trajectories during hematopoietic stem and progenitor cell (HSPC) differentiation to the erythroid, myeloid and lymphoid lineages, as well as during re-specification of cell identity by cellular reprogramming of monocytes and B-cells to HSPCs. CellRouter opens previously undescribed paths for in-depth characterization of complex cellular ecosystems and establishment of enhanced cell engineering approaches.

PMID: 29497036 [PubMed - indexed for MEDLINE]

Rare desmoplastic trichilemmoma associated with sebaceous nevus.

An Bras Dermatol. 2017 Nov-Dec;92(6):836-837

Authors: Jardim MML, Souza BCE, Fraga RC, Fraga RC

Abstract
Nevus sebaceous of Jadassohn is a congenital hamartoma that usually affects the scalp and face. Several benign or malignant neoplasias may develop in the lesion and the most common are trichoblastoma, syringocystadenoma papilliferum, and basal cell carcinoma. Trichilemmoma is a benign solid tumor originating from external sheath cells of pilosebaceous follicles. When it is characterized by a central zone of desmoplasia, it is called desmoplastic trichilemmoma. We report a case of a 58-year-old patient who developed a tumor in a sebaceous nevus. We performed a total excision of the lesion. Histopathological diagnosis was compatible with desmoplastic trichilemmoma. Our literature review reveals that the occurrence of trichilemmoma desmoplastic is unusual. Moreover, it can mimic an invasive carcinoma on histological and clinical examinations. This fact confirms the importance of reporting the occurrence of this rare cancer in a nevus sebaceous of Jadassohn.

PMID: 29364442 [PubMed - indexed for MEDLINE]

Toward better management of rare and orphan pulmonary diseases.

Eur Respir J. 2016 05;47(5):1334-5

Authors: Harari S, Humbert M

PMID: 27132268 [PubMed - indexed for MEDLINE]

Aging and neurodegeneration are associated with increased mutations in single human neurons.

Science. 2018 02 02;359(6375):555-559

Authors: Lodato MA, Rodin RE, Bohrson CL, Coulter ME, Barton AR, Kwon M, Sherman MA, Vitzthum CM, Luquette LJ, Yandava CN, Yang P, Chittenden TW, Hatem NE, Ryu SC, Woodworth MB, Park PJ, Walsh CA

Abstract
It has long been hypothesized that aging and neurodegeneration are associated with somatic mutation in neurons; however, methodological hurdles have prevented testing this hypothesis directly. We used single-cell whole-genome sequencing to perform genome-wide somatic single-nucleotide variant (sSNV) identification on DNA from 161 single neurons from the prefrontal cortex and hippocampus of 15 normal individuals (aged 4 months to 82 years), as well as 9 individuals affected by early-onset neurodegeneration due to genetic disorders of DNA repair (Cockayne syndrome and xeroderma pigmentosum). sSNVs increased approximately linearly with age in both areas (with a higher rate in hippocampus) and were more abundant in neurodegenerative disease. The accumulation of somatic mutations with age-which we term genosenium-shows age-related, region-related, and disease-related molecular signatures and may be important in other human age-associated conditions.

PMID: 29217584 [PubMed - indexed for MEDLINE]

Case of pediatric traditional serrated adenoma resected via endoscopic submucosal dissection.

World J Gastroenterol. 2017 Jun 28;23(24):4462-4466

Authors: Kondo S, Mori H, Nishiyama N, Kondo T, Shimono R, Okada H, Kusaka T

Abstract
Traditional serrated adenoma (TSA) is a type of serrated polyp of the colorectum and is thought to be a precancerous lesion. There are three types of serrated polyps, namely, hyperplastic polyps, sessile serrated adenomas/polyps, and TSAs. TSA is the least common of the three types and accounts for about 5% of serrated polyps. Here we report a pediatric case of TSA that was successfully resected by endoscopic submucosal dissection (ESD). This rare case report describes a pediatric patient with no family history of colonic polyp who was admitted to our hospital with hematochezia. On colonoscopy, we found a polypoid lesion measuring 10 mm in diameter in the lower rectum. We selected ESD as a surgical option for en bloc resection, and histopathological examination revealed TSA. The findings in this case suggest that TSA with precancerous potential can occur in children, and that ESD is useful for treating this lesion.

PMID: 28706430 [PubMed - indexed for MEDLINE]