The contributions of careful clinical observations: A legacy.

Clinical Medicine is an Art which is learned, together with hard work, as an apprentice-observing how a master works, and improving with experience and exposure. Clinicians are performing multiple things at the same time-trying to make a diagnosis, providing best therapies and preventative strategies, and looking for the underlying mechanism(s). Families want to know what to expect over time-the natural history of their disorder. Rare disease networks and parent support groups are helping in this effort. Information technologies and international collaborative efforts are changing the way clinical genetics is provided.

[«A most strange instance of illness in several siblings¼--first description of a rare neurological disease in 1830?]. / «Et høist mærkeligt Sygdomstilfælde hos flere Sødskende¼--en norsk førstegangsbeskrivelse fra 1830?

Was district medical officer Jensen the first doctor to describe patients with Pantothenate Kinase-Associated Neurodegeneration (PKAN) in Volda in 1830? A case series of four siblings with the same disease written by district medical officer Peter Jensen (1799-1832) in Aalesund in 1830, was published in the Norwegian medical journal Eyr in 1832. The children, who were healthy almost up to school age, developed dystonic involuntary movements and deformities in all extremities, lost their ability to speak and were emaciated before they died at around the age of nine years. Further information about the family and a fifth affected child has been found in the parish records. The clinical picture is consistent with Pantothenate Kinase-Associated Neurodegeneration (PKAN), a rare condition with basal ganglia iron deposition, described in 1922 by the German neuropathologists Julius Hallervorden (1882-1965) and Hugo Spatz (1888-1969). The disease was formerly called Hallervorden-Spatz syndrome, but because of the medical activities undertaken by these two researchers before and during the Second World War, this eponym is no longer recommended.

Healthcare-associated outbreaks due to Mucorales and other uncommon fungi.

BACKGROUND: Healthcare-associated outbreaks of fungal infections, especially with uncommon and emerging fungi, have become more frequent in the past decade. MATERIALS AND METHOD: Here, we reviewed the history and definition of healthcare-associated outbreaks of uncommon fungal infections and discussed the principles of investigating, containing and treatment of these outbreaks. RESULTS: In case of these uncommon diseases, occurrence of two or more cases in a short period is considered as an outbreak. Contaminated medical devices and hospital environment are the major sources of these outbreaks. Care must be taken to differentiate a real infection from colonization or contamination. Defining and identifying cases, describing epidemiologic feature of cases, finding and controlling the source of the outbreak, treating patients, and managing asymptomatic exposed patients are main steps for outbreak elimination. These fungal outbreaks are not only difficult to detect but also hard to treat. Early initiation of appropriate antifungal therapy is strongly associated with improved outcomes in infected patients. Choice of antifungal drugs should be made based on spectrum, pharmacodynamic and pharmacokinetic characteristics and adverse effects of available drugs. Combination antifungal therapy and surgical intervention may be also helpful in selected cases. CONCLUSIONS: A multidisciplinary approach and close collaboration between all key partners are necessary for successful control of fungal outbreaks.

The Digital Atlas of Ancient Rare Diseases (DAARD) and its relevance for current research.

BACKGROUND: The history of rare diseases is largely unknown. Research on this topic has focused on individual cases of prominent (historical) individuals and artistic (e.g., iconographic) representations. Medical collections include large numbers of specimens that exhibit signs of rare diseases, but most of them date to relatively recent periods. However, cases of rare diseases detected in mummies and skeletal remains derived from archaeological excavations have also been recorded. Nevertheless, this direct evidence from historical and archaeological contexts is mainly absent from academic discourse and generally not consulted in medical research on rare diseases. RESULTS: This desideratum is addressed by the Digital Atlas of Ancient Rare Diseases (DAARD: https://daard.dainst.org ), which is an open access/open data database and web-based mapping tool that collects evidence of different rare diseases found in skeletons and mummies globally and throughout all historic and prehistoric time periods. This easily searchable database allows queries by diagnosis, the preservation level of human remains, research methodology, place of curation and publications. In this manuscript, the design and functionality of the DAARD are illustrated using examples of achondroplasia and other types of stunted growth. CONCLUSIONS: As an open, collaborative repository for collecting, mapping and querying well-structured medical data on individuals from ancient times, the DAARD opens new avenues of research. Over time, the number of rare diseases will increase through the addition of new cases from varied backgrounds such as museum collections and archaeological excavations. Depending on the research question, phenotypic or genetic information can be retrieved, as well as information on the general occurrence of a rare disease in selected space-time intervals. Furthermore, for individuals diagnosed with a rare disease, this approach can help them to build identity and reveal an aspect of their condition they might not have been aware of. Thus, the DAARD contributes to the understanding of rare diseases from a long-term perspective and adds to the latest medical research.

Testing the Digital Atlas of Ancient Rare Diseases (DAARD) using a new case of Legg-Calvé-Perthes disease from Early Byzantine (500-700 CE) Olympia, Greece.

OBJECTIVE: The first case of Legg-Calvé-Perthes disease (LCPD) in Greece is presented. LCPD, a rare disease, is discussed using the Digital Atlas of Ancient Rare Diseases (DAARD), which tests the benefits of the database for diagnosing and contextualizing the new case with 42 archaeological cases of LCPD recorded in the DAARD. MATERIALS: A 30-40-year-old, probable male individual was found at the archaeological site of Olympia, Greece, dating to 500-700 CE. METHODS: Biological sex, age-at-death and pathological changes were investigated using macroscopic and osteometric methods. The DAARD provided the typical characteristics of LCPD. RESULTS: Pathological changes in both hip joints without any other related changes in the skeleton corresponded to the skeletal features of LCPD. The DAARD produced 42 cases of LCPD, most of which from Europe, with a preference for male sex and unilateral involvement of the hip joint. CONCLUSIONS: The DAARD aids in diagnosing rare diseases and interpreting new cases in the context of already known studies. SIGNIFICANCE: This study shows that the DAARD has the potential to help researchers move beyond the level of single case studies and create a broader picture of the history of rare diseases. LIMITATIONS: This paper focuses on the benefits of the DAARD in relation to LCPD but not all rare diseases have been included in the database. SUGGESTIONS FOR FURTHER RESEARCH: More rare diseases from archaeological contexts should be added to the DAARD to create a base for the interpretation of their history and expand our understanding of rare diseases in the past.

[Orphanet and its consortium: where to find expert-validated information on rare diseases]. / Orphanet et son réseau: où trouver une information validée sur les maladies rares.

There are approximately 6000 rare diseases, and 80% of them are genetic. In Europe, a disease is considered rare when it affects no more than one person in 2000. In France, two to three million people are affected, while nearly 30 million others are affected across Europe (5-8% of the whole European population). The majority of rare diseases are poorly understood by health professionals. Due to the lack of sufficient scientific and medical knowledge, many patients are misdiagnosed, which results in delays in care that can be harmful. Because many rare diseases are often associated with neurological manifestations, the neurologist in his daily practice may often encounter these complex diseases that require special care as well as a multidisciplinary approach. Orphanet is the reference portal for rare diseases. Freely accessible on the Internet, it is a non-profit service officially supported by the French Ministry of Health and the European Commission. Its mission is to keep healthcare professionals and patients informed and, by so doing, it contributes to improvements in the diagnosis and treatment of rare diseases. It is currently the only project that establishes a link between diseases and any published information concerning them, and the appropriate services for patients as well as healthcare professionals. Orphanet is currently the most comprehensive site in terms of referenced and documented data, and it has in just a few years become the global reference portal for rare diseases and orphan drugs for all audiences. Orphanet generates a million page views per month. The site is available in six languages (English, French, Spanish, Italian, German and Portuguese) and offers a range of services, including: an inventory, classification and peer-reviewed encyclopedia of rare diseases along with the associated genes (more than 2000 diseases with neurological manifestations are described); a diagnostic support tool; clinical and emergency guidelines; a directory of specialised services in 37 partner countries; an encyclopedia aimed at the general public; an inventory of orphan drugs; downloadable thematic studies and reports on such subjects as the prevalence of rare diseases, orphan drugs, aids and services for patients; and numerous links to other sources of information. Five to ten new rare diseases are described every month, which represents a major challenge for health professionals in terms of keeping their knowledge up to date. The Orphanet website content is expert-validated and updated continuously to respond in real time.

Environmental- and injury-related epidemic-assistance investigations, 1946-2005.

This paper summarizes environmental investigations (n = 458) conducted during the first 60 years of the epidemic-assistance investigation program at the Centers for Disease Control and Prevention. These investigations were grouped into 10 categories: toxic chemicals (n = 102), indoor air quality and outdoor air toxics (n = 21), new or rare epidemic diseases and unexplained syndromes (n = 29), natural disasters (n = 81), terrorism and unintentional human-made disasters (n = 9), substance use and abuse (n = 13), environmental aspects of infectious disease (n = 132), those affecting neonates and infants (n = 11), violence and injuries (n = 51), and miscellaneous (n = 9). Among the most important or prominent were studies of lead and arsenic toxicity at smelters, mercury in paint and beauty creams, dioxin in waste oil in Missouri, polychlorinated biphenyls and multiple other toxic chemicals, global pesticide poisoning outbreaks, hepatic angiosarcoma among vinyl chloride workers, toxic oil syndrome in Spain, eosinophilia-myalgia syndrome from contaminated L-tryptophan, diethylene glycol poisoning in Haiti, aflatoxicosis in Kenya, Gulf War illness among veterans, impact and needs assessments during natural disasters (e.g., Hurricane Katrina (2005) and the Mount St. Helens volcano eruptions (1980)), risk factors for heat-related mortality, domestic and international terrorist attacks, Parkinsonism related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in California, and unintentional injury- and violence-related events.

Cancers as rare diseases: Terminological, theoretical, and methodological biases.

OBJECTIVE: Was cancer a rare disease in the past? Our objective is to consider the various terminological, theoretical, and methodological biases that may affect perceptions of the rarity of cancer in the past. MATERIALS AND METHODS: We discuss relevant malignant neoplastic biomedical and paleopathological literature and evaluate skeletal data. We selected 108 archaeological sites (n = 151 cancer cases) with published malignant neoplasms and that were amenable to calculating cancer crude prevalence. Furthermore, datasets from four medieval/postmedieval Portuguese and 12 postmedieval UK sites were used to compare age-adjusted rates for metastatic bone disease and tuberculosis. RESULTS: In the literature review, mean cancer crude prevalence (1.2 %; 95 % CI = 0.96-1.4) exceeded the threshold for a rare disease (RD). Age-standardized rates of MBD and TB were not markedly different in the sites surveyed. CONCLUSIONS: Methodological, theoretical and historical factors contribute to assumptions that cancers were rare diseases. The assumption that cancers are extremely rare in the paleopathological literature was not fully supported. Cancer is a heterogeneous concept, and it is important to view it as such. If a disease is considered rare, we may fail to recognize it or dismiss it as unimportant in the past. SIGNIFICANCE: We present a re-evaluation of the idea that cancer is a rare disease. We present a more nuanced way of comparing rates of pathological conditions in archaeological contexts. LIMITATIONS: Variation in the amount of useable information in published literature on malignant neoplasms. SUGGESTIONS FOR FURTHER RESEARCH: More large-scale studies of cancer in the past alongside comparative studies of cancer prevalence with other assumed rare diseases.

Lasthénie de Ferjol syndrome: a rare disease with fascinating history.

In our paper, we present the fascinating story of Lasthénie de Ferjol syndrome. A rare self-induced iron deficiency anaemia caused by surreptitious blood-letting. The French haematologist Jean Bernard first described the syndrome and named it after the heroine of Barbey d' Aurevilly's novel The Story without a Name. This factitious anaemia presents a great challenge for physicians even today, both in diagnosis and in therapy.

Childhood rare lung disease in the 21st century: "-omics" technology advances accelerating discovery.

Childhood rare lung diseases comprise a large number of heterogeneous respiratory disorders that are individually rare but are collectively associated with substantial morbidity, mortality, and healthcare resource utilization. Although the genetic mechanisms for several of these disorders have been elucidated, the pathogenesis mechanisms for others remain poorly understood and treatment options remain limited. Childhood rare lung diseases are enriched for genetic etiologies; identification of the disease mechanisms underlying these rare disorders can inform the biology of normal human lung development and has implications for the treatment of more common respiratory diseases in children and adults. Advances in "-omics" technology, such as genomic sequencing, clinical phenotyping, biomarker discovery, genome editing, in vitro and model organism disease modeling, single-cell analyses, cellular imaging, and high-throughput drug screening have enabled significant progress for diagnosis and treatment of rare childhood lung diseases. The most striking example of this progress has been realized for patients with cystic fibrosis for whom effective, personalized therapies based on CFTR genotype are now available. In this chapter, we focus on recent technology advances in childhood rare lung diseases, acknowledge persistent challenges, and identify promising new technologies that will impact not only biological discovery, but also improve diagnosis, therapies, and survival for children with these rare disorders.

New problems of a new health system: the creation of a national public policy of rare diseases care in Brazil (1990s-2010s). / Nuevos problemas de un nuevo sistema de salud: la creación de una política pública nacional de atención de enfermedades raras en Brasil (1990-2014).

This study discusses actors and institution movements leading to the disclosure in 2014 of Resolution 199 by the Brazilian Ministry of Health, which establishes the National Policy for the Comprehensive Care of Persons with Rare Diseases. Taking as sources the mainstream newspapers, drafts law, and secondary literature on the subject, we begin our analysis in the early 1990s when the first patient associations were created in Brazil - mainly for claiming more funds for research on genetic diseases - and arrive at the late 2010s when negotiations for a national policy are taking place in the National Congress. Resolution 199 is part of an ongoing process and the path towards its disclosure and the complications that followed have given us elements to discuss contemporary aspects of the Brazilian public health. Based on the references of the history of the present time and the social studies of science, we argue that two aspects have been fundamental to creating a national policy: framing different illnesses within the terminology "rare diseases" and the construction of a public perception about the right of health which is guaranteed by the 1988 Brazilian Constitution.

En este trabajo se analizan los movimientos de actores e instituciones que llevaron a la promulgación, en 2014, de la Resolución 199 del Ministerio de Salud de Brasil, que establece la Política Nacional de Atención Integral a las Personas con Enfermedades Raras. Tomando como fuentes los principales periódicos, proyectos de ley y bibliografía secundaria sobre el tema, comenzamos nuestro análisis a principios de la década de 1990 con la creación de las primeras asociaciones de pacientes en Brasil, para reclamar fundamentalmente más fondos para la investigación de enfermedades genéticas, y llegamos a fines de la década de 2010 con las negociaciones para una política nacional. La Resolución 199 es parte de un proceso en curso, en el que el camino hacia la promulgación y las complicaciones posteriores nos dan elementos para discutir aspectos actuales de la salud pública brasileña. Sobre la base de la historia del tiempo presente y los estudios sociales de la ciencia, argumentamos que hay dos aspectos que han sido fundamentales para crear una política nacional: enmarcar diferentes enfermedades en la terminología "enfermedades raras" y la construcción de una percepción pública sobre el derecho a la salud, que se garantiza en la Constitución brasileña de 1988.

How did uncommon disorders become 'rare diseases'? History of a boundary object.

The category of 'rare diseases' has been in growing use in the fields of public health and patient advocacy for the past 15 years in Europe. In this socio-historical inquiry, I argue that this category, which appeared initially as a by-product of the orphan drug issue in the United States of America, is a boundary object. As such, it has different specific local uses: a meaningless category for physicians, it relates to the patients' experience of illness, whereas the pharmaceutical industry first considered it as being synonymous with small markets and then with innovation. Public bodies contributed to framing a common and blurred use, based on a statistical definition whose purpose was to foster co-operation between the four groups involved in the issue. In the definition process of the category of rare diseases, the key actors were the patients and public bodies, not medical professionals or the pharmaceutical industry.

Insulinoma: a rare neuroendocrine pancreatic tumor.

Insulinomas are functional endocrine tumors originating from the pancreatic b-cells. In 1902 Nicholls described the first adenoma of pancreatic islets, while the first insulinoma was described in 1927 in Mayo Clinic, which was dissected two years later in 1929 in Toronto. The first enucleation of insulinoma took place in a St. Jouis hospital in 1931, and after four years, in 1935, Whipple described the classic diagnostic triad: symptoms of fasting hypoglycemia or fatigue, blood glucose levels under 50 mg/dl and disappearance of symptoms after glucose administration.

Esophageal atresia, Europe, and the future: BAPS Journal of Pediatric Surgery Lecture.

Europe has changed remarkably over the past decades and so have concepts and outcomes of esophageal atresia repair. In this article, both the efforts to create a united Europe and the achievements in dealing with esophageal atresia from the 1950s on are outlined. Furthermore, this paper deals with the future of pediatric surgery and is focused on two aspects: the "Fourth Industrial Revolution" which builds on the digital revolution, artificial intelligence and robotics, and its potential impact on pediatric surgery and the life of patients. I suggest that pediatric surgeons should participate and lead in the development of machine learning, data control, assuring appropriate use of machines, control misuse, and in particular ensure appropriate maintenance of ethical standards. Changes in health care structures within Europe, in particular the effect of centralization, will affect the concept of treatment for patients with rare diseases.

Amniotic fluid embolism: historical perspectives & new possibilities.

Amniotic fluid embolism (AFE) is a rare obstetric catastrophe that occurs suddenly and without warning. AFE is a condition that is poorly understood and often difficult to diagnose, but has a high maternal and neonatal morbidity and mortality. Since it was first described in 1926, the underlying pathophysiology has eluded researchers and clinicians. While a new understanding of the syndrome has emerged with the advent of a national registry in the 1980s, recommendations for diagnostic methods and treatment in the acute phase of the event remain unclear. The purpose of this article is to provide the reader with a historical look at the phenomenon of AFE, a description of its suspected pathophysiology, and recommendations for nursing interventions. A review of data from the national registry and other classic studies are included.

Rare diseases and orphan drugs: 500 years ago.

In 1581 Rembert Dodoens wrote "Medicinalium observationum exempla rara, recognita et aucta" a Latin book about the diagnosis and treatment of disorders with a low prevalence.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a historical perspective.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital defect of the Müllerian ducts characterized by uterovaginal agenesis and underdeveloped female genital organs. This paper is a tribute to the contributors of this condition - August Franz Joseph Karl Mayer, Karl Freiherr von Rokitansky, Hermann Küster and Georges André Hauser. In addition to their contributions, we have discussed findings and reports of similar defects from other important scientists (Hippocrates, Albucasis, etc.) dating as far back as 460B.C. We have also discussed the disease types and different classification systems including VCUAM and AFS/ASRM among others. Even with several surgical and non-surgical treatment options, there are still many questions that remain unanswered and very little is known about the etiology or genetic predisposition of this condition.