New insights into the evaluation of randomized controlled trials for rare diseases over a long-term research horizon: a simulation study.

Stat Med. 2016 Aug 30;35(19):3245-58

Authors: Bayar MA, Le Teuff G, Michiels S, Sargent DJ, Le Deley MC

Abstract
Large sample sizes are required in randomized clinical trials designed to meet typical one-sided 2.5% α-level and 80% power. This may not be achievable when the disease is rare. We simulated a series of two-arm superiority trials over a 15-year period. The design parameters examined were the α-level and the number of trials conducted over the 15-year period (thus, trial sample size). Different disease severities and accrual rates were considered. The future treatment effect was characterized by its associated hazard rate; different hypotheses of how treatments improve over time were considered. We defined the total survival benefit as the relative difference of the hazard rates at year 15 versus year 0. The optimal design was defined by maximizing the expected total survival benefit, provided that the risk of selecting at year 15 a treatment inferior to the initial control treatment remains below 1%. Compared with two larger trials with typical one-sided 2.5% α-level, performing a series of small trials with relaxed α-levels leads on average to larger survival benefits over a 15-year research horizon, but also to higher risk of selecting a worse treatment at the end of the research period. Under reasonably optimistic assumptions regarding the future treatment effects, optimal designs outperform traditional ones when the disease is severe (baseline median survival ≤ 1 year) and the accrual is ≥100 patients per year, whereas no major improvement is observed in diseases with better prognosis. Trial designs aiming to maximize survival gain over a long research horizon across a series of trials are worth discussing in the context of rare diseases. Copyright © 2016 John Wiley & Sons, Ltd.

PMID: 27027783 [PubMed - indexed for MEDLINE]

Pediatric Pulmonology year in review 2016: Part 1.

Pediatr Pulmonol. 2017 Sep;52(9):1226-1233

Authors: Birnkrant DJ, Black JB, Tapia IE, Nicolai T, Gower WA, Noah TL

Abstract
Pediatric Pulmonology continues to publish research and clinical topics related to the entire range of children's respiratory disorders. As we have done annually in recent years, we here summarize the past year's publications in our major topic areas, as well as selected literature in these areas from other core journals relevant to our discipline. This review (Part 1) covers selected articles on sleep, diagnostic testing/endoscopy, respiratory complications of neuromuscular disorders, and rare lung diseases.

PMID: 28440921 [PubMed - indexed for MEDLINE]

A rare case of renal thrombotic microangiopathy associated with Castleman's disease.

BMC Nephrol. 2017 Feb 10;18(1):57

Authors: Mutneja A, Cossey LN, Liapis H, Chen YM

Abstract
BACKGROUND: Castleman's disease (CD) is an uncommon, heterogeneous lympho-proliferative disorder leading to high circulating levels of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF). Renal involvement has been only described in a limited number of small studies. Herein, we report a rare case of renal thrombotic microangiopathy (TMA) associated with CD and investigate the podocyte expression of VEGF in the renal biopsy prior to initiation of treatment.
CASE PRESENTATION: An 18-year-old male presented with fever, diarrhea, diffuse lymphadenopathy, ascites and acute kidney injury. Laboratory tests for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura were negative. The kidney biopsy showed TMA. An excisional lymph node biopsy was consistent with CD, plasma cell variant. Immunofluorescence staining showed suppressed podocyte VEGF expression. Chemotherapy that inhibits production of inflammatory mediators including IL-6 and VEGF led to complete recovery of renal function.
CONCLUSIONS: Our case illustrates a rare renal histological feature of CD. IL-6 and VEGF are postulated to suppress glomerular VEGF expression, thereby causing renal TMA. Therapy directed against these inflammatory mediators may have important therapeutic implications.

PMID: 28183278 [PubMed - indexed for MEDLINE]

[To reimburse or not? Evaluating expensive drugs differently].

Ned Tijdschr Geneeskd. 2016;160(0):D1022

Authors: Stolk J

Abstract
Health insurance organisations grant reimbursement for drug treatment on the basis of results of placebo-controlled randomised clinical trials showing a clinically meaningful and statistically significant effect over placebo. This often proves problematic in rare diseases as well as in many chronic diseases that are difficult to treat. Clinical scientists may address the issue by testing the drug on surrogate outcome parameters and ask for post-marketing studies conducted by expert reference centres as expediency research, using budgets provided by the government to show that the drug really works in terms of real-life patient experience. In the past 5 years, the pharmaceutical industry has released an increasing number of expensive drugs for rare diseases; this jeopardises the solidarity of health insurance cover for all EU citizens. To facilitate drug development, a new model might benefit all key players involved. The foundation Fair Medicine recently called for coalitions that jointly develop medicines based on contribution and complementarity, sharing responsibilities, risks and rewards.

PMID: 27879186 [PubMed - indexed for MEDLINE]

[Kleine Levin Syndrome: more than just periodic hypersomnia].

Ned Tijdschr Geneeskd. 2016;160:D238

Authors: Pillen S, Vandenbussche NL, Fronczek R, van Duijn J, Lammers GJ, Overeem S

Abstract
BACKGROUND: Kleine Levin Syndrome (KLS) is a rare disease with periodic hypersomnia as its main feature. Hyperphagia and hypersexuality are also described as classical symptoms, although quite recently it has become clear that the full triad is absent in the majority of patients.
CASE DESCRIPTION: A 14-year-old boy developed KLS after a period of flu-like symptoms. Over the course of three years he suffered from seven one-week episodes of extreme hypersomnia (sleeping 18 hours a day), depersonalisation, apathy, anxiety, paranoia, confusion, hallucinations and uninhibited sexual behaviour. He ate little. Ancillary investigations did not reveal any abnormalities. In between these episodes he had no symptoms.
CONCLUSION: From this case description and a summary of the symptoms of twelve other patients with KLS, it appears that neuropsychiatric symptoms are much more prominent than hyperphagia and hypersexuality. It is important that the typical KLS phenotype be reappraised, so that the condition can be recognised early and patients managed appropriately.

PMID: 27484420 [PubMed - indexed for MEDLINE]

FATCO Syndrome (Fibular Aplasia, Tibial Campomelia, Oligosyndactyly with Talar Aplasia). A Case Study.

Ortop Traumatol Rehabil. 2017 Jan 26;19(1):75-78

Authors: Ahmad K, Ahmad Malla H, Dawood S

Abstract
FATCO syndrome consists of fibular hemimelia, tibial campomelia and oligosyndactyly. FATCO syndrome can also be associated with other congenital anomalies; therefore, every case needs thorough evaluation so as to make the management of the patient easier. A few cases of this syndrome have been described in literature but only two cases have been reported in India so far. We present a 3-year-old male child born of a non-con-sanguinous marriage with FATCO syndrome and ipilateral talar aplasia without any other congenital anomalies.

PMID: 28436373 [PubMed - indexed for MEDLINE]

Evaluating the Calling Performance of a Rare Disease NGS Panel for Single Nucleotide and Copy Number Variants.

Mol Diagn Ther. 2017 Jun;21(3):303-313

Authors: Cacheiro P, Ordóñez-Ugalde A, Quintáns B, Piñeiro-Hermida S, Amigo J, García-Murias M, Pascual-Pascual SI, Grandas F, Arpa J, Carracedo A, Sobrido MJ

Abstract
INTRODUCTION: Variant detection protocols for clinical next-generation sequencing (NGS) need application-specific optimization. Our aim was to analyze the performance of single nucleotide variant (SNV) and copy number (CNV) detection programs on an NGS panel for a rare disease.
METHODS: Thirty genes were sequenced in 83 patients with hereditary spastic paraplegia. The variant calls obtained with LifeScope, GATK UnifiedGenotyper and GATK HaplotypeCaller were compared with Sanger sequencing. The calling efficiency was evaluated for 187 (56 unique) SNVs and indels. Five multiexon deletions detected by multiple ligation probe assay were assessed from the NGS panel data with ExomeDepth, panelcn.MOPS and CNVPanelizer software.
RESULTS: There were 48/51 (94%) SNVs and 1/5 (20%) indels consistently detected by all the calling algorithms. Two SNVs were not detected by any of the callers because of a rare reference allele, and one SNV in a low coverage region was only detected by two algorithms. Regarding CNVs, ExomeDepth detected 5/5 multi-exon deletions, panelcn.MOPs 4/5 and only 3/5 deletions were accurately detected by CNVPanelizer.
CONCLUSIONS: The calling efficiency of NGS algorithms for SNVs is influenced by variant type and coverage. NGS protocols need to account for the presence of rare variants in the reference sequence as well as for ambiguities in indel calling. CNV detection algorithms can be used to identify large deletions from NGS panel data for diagnostic applications; however, sensitivity depends on coverage, selection of the reference set and deletion size. We recommend the incorporation of several variant callers in the NGS pipeline to maximize variant detection efficiency.

PMID: 28290094 [PubMed - indexed for MEDLINE]

[The place of neuropathy in the early diagnosis of Cockayne syndrome: Report on two siblings].

Arch Pediatr. 2017 Apr;24(4):353-359

Authors: Blin-Rochemaure N, Allani-Essid N, Carlier R, Laugel V, Quijano-Roy S

Abstract
Two siblings affected with Cockayne syndrome (CS) are described: this diagnosis was suggested by the finding of a demyelinating neuropathy on electromyography in both children and consistent clinical features. CS is a rare genetic disorder with severe prognosis and a highly varied phenotype, making early diagnosis difficult. Taking into account these two cases and the literature, the current diagnosis criteria are insufficiently specific and appear late: the diagnosis may be delayed because multi-organ involvement and sensorial impairment suggests more frequent neurometabolic disorders. Neuroradiologic abnormalities are suggestive but may occur later. The finding of a demyelinating peripheral neuropathy seems to be a more useful marker to suspect this disorder in the presence of other clinical features. Further studies are required to better define the chronology of the symptoms, not only for adequate genetic counseling and eventual prenatal diagnosis, but also to assess the efficacy of future therapies.

PMID: 28258862 [PubMed - indexed for MEDLINE]

[Chronic vulvar lymphedema revealing Crohn disease in a teenage girl].

Arch Pediatr. 2017 Apr;24(4):346-349

Authors: Aounallah A, Ghariani Fetoui N, Ksiaa M, Boussofara L, Saidi W, Mokni S, Sriha B, Belajouza C, Denguezli M, Ghariani N, Nouira R

Abstract
INTRODUCTION: Cutaneous Crohn disease is a rare cutaneous manifestation of Crohn disease in children. Herein is reported a case of persistent vulvar lymphedema revealing Crohn disease in a teenage girl.
CASE REPORT: A 14-year-old girl presented with an 8-month history of persistent vulvar swelling associated with chronic macrocheilia. Dermatologic examination showed an inflammatory vulvar lymphedema, associated with perianal fissures and hypertrophic gingivitis. Vulvar skin biopsy revealed non-necrotizing granulomatous inflammation. Gastrointestinal endoscopy yielded no significant findings. The diagnosis of Crohn disease presenting as vulvar lymphedema was established. Oral metronidazole therapy resulted in partial improvement of cutaneous lesions beginning the 1st week.
CONCLUSION: The originality of this case lies in the presentation of chronic macrocheilia with persistent vulvar lymphedema in a child, revealing Crohn disease without gastrointestinal involvement.

PMID: 28233720 [PubMed - indexed for MEDLINE]

[A Rare Form of Oral Leukoplakia].

Laryngorhinootologie. 2017 01;96(1):43-44

Authors: Steinbichler TB, Moser P, Dudas J, Gassner R, Riechelmann H

PMID: 27978585 [PubMed - indexed for MEDLINE]

Multimodality imaging-based evaluation of Rosai-Dorfman disease in the head and neck: A retrospective observational study.

Medicine (Baltimore). 2017 Dec;96(51):e9372

Authors: Xu Q, Fu L, Liu C

Abstract
Rosai-Dorfman disease (RDD) is an uncommon benign entity characterized histologically by lymphatic sinus dilatation due to histiocyte proliferation. This study was performed to delineate its imaging features, reviewed retrospectively in 12 patients (8 women and 4 men, mean age 58.2 years [range 27-84]) with pathologically confirmed RDD in the head and neck. The location, involvement, and imaging characteristics (CT, magnetic resonance imaging (MRI), and PET/CT) of all lesions were evaluated. Signal intensity on MRI images was compared to gray matter (orbital RDD) and adjacent muscle (sinonasal and cervical RDD). RDD in the head and neck involved multiple sites, primarily the sinonasal cavity (n = 7), neck (n = 3), and orbit (n = 1), with one case of simultaneous involvement of the sinonasal cavity, orbit, and neck. With sinonasal involvement, MRI signal intensity of the involved areas was isointense or slightly hyperintense relative to adjacent muscle on T1WI images and heterogeneous on T2WI images; with lacrimal involvement, it was isointense relative to gray matter on T1- and T2-weighted images; and with neck involvement, it was isointense relative to muscle on T1WI images and relatively hyperintense on T2WI images, with homogenous postcontrast enhancement in all sites of involvement. The lesions on CT were observed as enhancing masses with or without bony destruction. PET/CT showed hypermetabolism in one lesion in the neck. RDD is a rare disorder with multiple sites of involvement in the head and neck. Concomitant cervical lymphadenopathy with extranodal masses assisted by multimodal imaging may be useful in the diagnosis of RDD.

PMID: 29390533 [PubMed - indexed for MEDLINE]

Dexmedetomidine-based monitored conscious sedation combined local anesthesia for levator resection in a 10-year-old child with Marcus Gunn jaw-winking synkinesis: A case report.

Medicine (Baltimore). 2017 Dec;96(51):e9369

Authors: Tu Y, Gao F

Abstract
RATIONALE: Levator resection has become a routine procedure for patients with severe Marcus Gunn jaw-winking synkinesis (MGJWS). To optimize the surgical outcome, adult patients need to be kept awake, or easily aroused and responsive to verbal commands during the operation. However, levator resection is commonly performed under general anesthesia in pediatric patients. In the present case, we described a successful anesthetic protocol of conscious sedation with local anesthesia for levator resection in a child.
PATIENT CONCERNS: A 10-year-old boy with MGJWS was admitted to our hospital and scheduled for levator resection. The patient was born through a normal delivery and had no previous history of allergy, no comorbidity, and no history of receiving anesthesia or operation. The laboratory tests of the patient were unremarkable.
DIAGNOSES: The diagnosis of MGJWS was made by two experienced ophthalmologists.
INTERVENTIONS: A 10-year-old boy with MGJWS was admitted to our hospital and scheduled for levator resection. The levator resection was performed under monitored conscious sedation with dexmedetomidine and local anesthesia.
OUTCOMES: Patient with spontaneous breathing responded normally to verbal commands throughout the operation, and no adverse events occurred. The patient and ophthalmologist reported high satisfaction with anesthesia management.
LESSONS: Dexmedetomidine-based monitored conscious sedation with local anesthesia is a feasible alternative to general anesthesia for levator resection in collaborative patients.

PMID: 29390531 [PubMed - indexed for MEDLINE]

Solitary fibrous tumor of the ilium: A case report.

Medicine (Baltimore). 2017 Dec;96(51):e9355

Authors: Ge X, Liao J, Choo RJ, Yan J, Zhang J

Abstract
RATIONALE: Solitary fibrous tumors (SFTs) are rare spindle cell tumors that are most commonly found in the mediastinal pleura. Although there are increasingly more reports of extra-pleural SFTs, reports of SFTs in bone are very rare. To our knowledge, a SFT of the ilium has not yet been reported. With low specificity on computer tomograpy and magnetic resonance imaging, SFTs are easily misdiagnosed.
PATIENT CONCERNS: A 33-year-old man visited our hospital due to repeated right ilium pain for 3 months. The pain was dull and bearable, with no hip joint dyskinesia. The relevant physical examinations are negative. The patient was healthy before and had a negative family history. Radiologically, a large mass with inhomogeneous attenuation and intensity and obvious heterogeneous enhancement was misdiagnosed as a giant cell tumor of ilium.
DIAGNOSES: The man was diagnosed as the solitary fibrous tumor of right ilium.
INTERVENTIONS: The patient was performed an "incision biopsy of the right ilium" and "extended resection of tumor".
OUTCOMES: The pathology and immunohistochemistry was confirmed as the solitary fibrous tumors. The patient was followed-up by computed tomography of pelvis in local hospital every 6 mouths, and there is no recurrence and any symptoms.
LESSONS: We learned that the solitary fibrous tumor could locate in the ilium, and when we see imaging manifestations like this case, we should think it may be SFT.

PMID: 29390521 [PubMed - indexed for MEDLINE]

Cervical digit in a child: A case report.

Medicine (Baltimore). 2017 Dec;96(51):e9348

Authors: Tong MJ, Xiang GH, He ZL, Xu HZ, Tian NF

Abstract
BACKGROUND: A "digit-like" bone is a rare developmental anomaly that is usually seen in the pelvic or thoracic regions. Such an anomaly in the cervical spine is extremely rare and few cases have been reported. We present a patient with an anomalous bone posterior to a cervical vertebra. The patient was admitted to our hospital with a gradually growing hard neck mass and esthetic complaints. Physical examination, radiographs, reconstructed computed tomography, and magnetic resonance imaging revealed a digit-like bone posterior to the cervical spine. The patient was diagnosed with a "cervical digit." Through a posterior midline approach, the anomalous bone was excised because of its gradually increasing size and esthetic complaints.
RESULTS: Intraoperatively, the bony mass was found to have a pseudoarticulation with the spinous process of C5 (the fifth cervical vertebra). The specimen consisted of normal bone and cartilage. The child returned to a normal life postoperatively with no symptoms. There was no recurrence at the 2-year follow-up.
CONCLUSION: A congenital cervical digit is a rare deformity. A detailed clinical workup and advanced imaging examinations are useful for diagnosing such conditions. Esthetic complaints contribute to surgical indications. This is the first cervical digit managed with surgical excision of the anomalous bone and had a favorable outcome.

PMID: 29390517 [PubMed - indexed for MEDLINE]

A novel pathogenic mutation in RPL11 identified in a patient diagnosed with diamond Blackfan anemia as a young adult.

Blood Cells Mol Dis. 2016 10;61:46-7

Authors: Narla A, Yuan D, Kazerounian S, LaVasseur C, Ulirsch JC, Narla J, Glader B, Sankaran VG, Gazda H

PMID: 27667165 [PubMed - indexed for MEDLINE]

I Am That Parent.

JAMA. 2018 Feb 06;319(5):445

Authors: Rule ARL

PMID: 29411036 [PubMed - indexed for MEDLINE]

The decision-making process and criteria in selecting candidate drugs for progeria clinical trials.

EMBO Mol Med. 2016 07;8(7):685-7

Authors: Gordon LB, Kieran MW, Kleinman ME, Misteli T

PMID: 27234439 [PubMed - indexed for MEDLINE]

[Aplasia cutis congenita is a rare and possibly overlooked congenital anomaly].

Ugeskr Laeger. 2014 Nov 24;176(48):

Authors: E Rogvi R, Sommerlund M, Vestergaard ET

Abstract
Aplasia cutis congenita (ACC) is a rare congenital defect of the skin. In this study we present the diagnosis and management of the condition. In 1997-2009 a total of 65 ACC cases were registered in the Danish National Patient Registry (1:13.000 births). The mortality among these cases was 1.6% (one case) though the death was not attributable to ACC, which is far lower than described in international studies.

PMID: 25430571 [PubMed - indexed for MEDLINE]

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[Patient with homozygous sickle cell disease and free flap surgery: Ensuring the success of the procedure].

Ann Chir Plast Esthet. 2017 Apr;62(2):171-175

Authors: Deneuve S, Maire L, Bachelot V, Dammacco MA, Zrounba P, Delay E

Abstract
Sickle cell anaemia is rare in France but frequent in Africa, leading to rigid, sickle-like shape red blood cells which bind together blocking microcirculation under certain circumstances. The vaso-occlusive crisis is the most frequent clinical manifestation especially in case of homozygous disease. Sickle cells disease is therefore usually considerated as a contraindication to microsurgery, however sometimes, a free flap procedure is mandatory. We here report the case of a 47-year-old man suffering with homozygous sickle cell anaemia and needing an antebrachial free flap procedure for a tongue reconstruction. The postoperative course was unremarkable apart from a delayed healing which is common in this particular localization. A review of the litterature allows to list the precautions to be taken to ensure a microsurgical procedure with this medical background. The preoperative examination has to assess usual sickle cell disease comorbidities such as kidney failure, heart failure or pulmonary hypertension. All the events leading to either low output syndrome, hypoxia, hypothermia, or a stress caused by uncontrolled pain should be avoided per- and postoperatively. With an optimum medical care, microsurgery is possible even in patients suffering with sickle cells anaemia. This case is rare in France but will become frequent in Africa with the improvement of the healthcare system, allowing to give all patients the best medical care.

PMID: 27692921 [PubMed - indexed for MEDLINE]