American J o u r n a l of Medical Genetics 39:342-346 (1991)
Syndrome: Le Mot de Jour Stanley Jablonski
Syndrome is one of the oldest terms in the medical vocabulary. It has been used as a designation for those disorders that were marked by etiologically nonspecific similar groups of manifestations up to the time of Sydenham. His contention that the terms syndrome and disease were in fact synonymous explains in part infrequent use of syndrome in the literature until the latter part of the 19th century. Redefinition of syndrome early in the 20th century as a disorder characterized by the concurrence of symptoms which are causally related, and further refinement of the definition as a condition marked by a cluster of symptoms occurring together coincidentally, gradually restored the popularity of the term to where syndrome is now one of the most frequently used designations of morbid states in the literature. There are numerous definitions of syndrome currently in use. One which is accepted by most dysmorphologists, geneticists, and some clinicians states that syndrome is an etiologically defined entity of unknown pathogenesis. However, most writers use the term randomly to denote any abnormal condition, whether medical, social, or behavioral, when a more satisfactory designation cannot be found or created, or to emphasize special complexity (syndromic qualities?) of already named diseases, or merely to be amusing. The post-Sydenham custom of naming of syndromes after physicians gave way in the mid-20th century to methods wherein syndrome names incorporate clinical, etiological, genetic, and other significant characteristics. Other methods used in designating syndromes include using the names of the first patient known to be affected, acronyms and abbreviations, personal names of all kinds, and the like. Syndrome, once a unique and valuable term in the
arsenal of medical vocabulary, has lost much of its usefulness through misuse.
KEY WORDS: syndrome, history, terminology
The word syndrome (from Greek syn together and d r h o s a course [Latin concursusl) means concurrence; things running together. It is one of the oldest terms in the medical vocabulary, and said to have been used by Hippocrates and Galen [Castelli, 1775; Murray et al., 19191. A definition in Motherby’s dictionary [I8611 (an adaptation from Castelli’s Lexicon Medicorum GraecoLatinum, describes syndrome as a term which was . . introduced by the sect of empiric physicians to express the concourse of congeries of symptoms: for instance, the concourse of symptoms when diseases arise from plethora, are called plethoric syndrome. So may there be a cacochymic syndrome; and indeed it may apply less generally, as a choleric, phlegmatic, pleuritic, epileptic syndrome &c.” By the end of the 19th century, definitions became more to the point. In his dictionary, Billings [18901, defined the term as “a name denoting the aggregate of symptoms of disease,” and Dorland [19001 defined it a s a “complex of symptoms; a set of symptoms that occur together; a sum of signs of any morbid state.” Dorland‘s definition, although somewhat modified is still used in most medical dictionaries. Through the 19th and the first half of the 20th centuries, the term syndrome was used in the medical literature to name disorders characterized by multiple symptoms with a tendency to occur together, and involved various, sometimes apparently unrelated, organs and systems, which frequently occurred without any immediately explainable cause. That is, disorders which baffled physicians and, in spite of their considerable linguistic skills, defied their ability to coin appropriate terms by means of combining word fragments into a single designation, as would have been possible with other, less complex, conditions. Whenever enough was known about a disorder, the available information would Received for publication May 9, 1990; revision received October have been incorporated into the term which was then appended by syndrome. Otherwise, the syndrome was 10, 1990. named after the physician believed to have originally Address reprint requests to Stanley Jablonski, 8603 Virginia described it. Thomas Sydenham’s redefinition of the Avenue, Annandale, VA 22003. S.Jablonski was formerly with the National Library of Medicine term disease represents a n early, although indirect, attempt at restricting the meaning of the term syndrome. in Bethesda, Maryland.
0 1991 Wiley-Liss, Inc.
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Syndrome Before Sydenham, disease denoted the subjective state of a n ill person, whereas syndrome referred to the signs and symptoms listed by the physician. According to Syndenham’s definition, both terms are synonymous, thus rendering syndrome superfluous and, in part, explaining its relative infrequent use until the latter part of the 19th century [Spranger, 19891. The scope of the definition of syndrome was further narrowed in 1921by Pfaundler and von Seht [1922], who coined the term syntropy (from Greek syn together, with, tropos a turning; turning toward each other) to encompass those disorders which are characterized by the concurrence of symptoms that are causally related; thus dividing syndromes into those which are marked by symptoms which have a common cause and those which do not. This refinement was further advanced by Gunther [1948], who defined syndrome as a disorder that is marked by a cluster of symptoms occurring together coincidentally; not to be confused with symptom complex, which is a manifestation of disease, the symptoms being caused by the underlying disease. Gunther used the occasion to deplore the deterioration of scholarship in medicine, pointing out that the Greek feminine noun syndrome is incorrectly translated into modern languages, such as le syndrome (masculine noun) in French and das Syndrom (a neuter noun) in German. His suggestion t h a t the German Syndrom should be replaced by the more appropriate die Syndromie (English syndromy) never gained popular acceptance. There are numerous, sometimes conflicting, definitions of the term syndrome now in use. 1. A set of symptoms which occur together; the sum of signs of any morbid state; a symptom complex. In genetics, a pattern of multiple malformations [Dorland’s Illustrated Medical Dictionary, 19881. 2. In general medicine, syndrome is synonymous with symptom complex [Warkany, 19741. 3. A constant unhealthy coexistence of abnormal symptoms and signs whose relationships to underlying disorders are obscure [Smith, 19651. 4. Apparently specific clinical disorder of multiple defects. If and when the more basic etiology has been clarified, then the disorder might be considered a specific disease entity [Smith, 19741. 5. (a)The pattern of symptoms that characterizes a particular disorder or disease. . . ; (b) loosely, a cluster of characteristics; a set of behaviors believed to have a common cause or basis [English and English, 19581. 6. A congenital syndrome is generally considered to be: constellation of abnormalities due to a single developmental or genetic defect [Hirschhorn, 19811. 7. . . . a n etiologically defined entity of unknown pathogenesis [Spranger, 19891. (Not to be confused with disease, symptom complex, or sequence.) Further attempts to standardize the meaning of syndrome resulted in additional terms and definitions. 8. Syndrome definition-“The elucidation the cause of syndrome” [Spranger, 19891. 9. Syndrome delineation-“The study of the phenotype and natural history of the syndrome” [Opitz et al., 19791.
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10. Causal (true) syndromy [syndrome]-“. . . a causally defined pleiotropic disorder” [Opitz et al., 19791. 11. False syndromy [syndrome]--“ . . . includes coincidental and associational syndromy, i.e., types of syndromy that do not represent pleiotropy or other developmentally and/or functionally correlated manifestations of a single cause such a s mendelian mutation, chromosome abnormality, or teratogenic agents” [Opitz et al., 19791. 12. Assocational syndromy [syndrome] or association-“ . . . a variety of false syndromy in which two or more manifestations in the patient (or his family or both) represent noncausal concurrence, due either to linkage or to a linkage-disequilibrium situation” [Opitz et al., 19791. 13. “ . . . a nonrandom association of defects which cannot be interpreted as the consequence of a single primary localized defect in morphogenesis or delineation as a specific syndrome or disease in terms of the total clinical findings and etiology” [Smith, 19791. 14. Hippocratic (symptomatic) syndromy [syndrome]-“ . . . refers to patients with etiologically nonspecific similar or identical sets of manifestations . . . It is presumed that the several manifestations or symptoms of the patients are due to a single cause that varies from patient to patient, though their conditions may be very similar. . . that seems to have the original use of the term from Hippocrates through Galen to the days of Sydenham” [Opitz et al., 19791. 15. Formal genesis syndromy [syndrome]-One that is pathogenically defined [Opitz et al., 19791. 16. Causal genesis syndromy [syndrome]-“Initially the use of this was restricted to multiple manifestations (mostly structural) of mendelian mutation . . . we think it is quite appropriate to extend the use ofthe term to the multiple developmental manifestations of chromosome mutation as well, while keeping in mind that their effect is or may be produced in a developmentally different manner than in the case of, say a complex autosomal recessive t r a i t . . . ” [Opitz et al., 19793. 17. Physical examination syndrome-“The patient in whom the first particular combination of physical manifestations has been observed can be said to have physical examination syndrome” [Opitz et al., 19791. 18. Private syndrome-“A malformation syndrome due to a n apparently unique chromosome rearrangement which may or may not segregate in a family” [McKusick, 19741. 19. Provisionally private syndrome--“ . . . refers to two or more sibs with the same malformation syndrome, nonconsanguineous parents, and with apparently normal karyotype in patients and parents” [McKusick, 19741. 20. Public syndrome--“A malformation syndrome due to chromosomal abnormalities which recur with a specific frequency in the population (e.g., trisomy, centric fusion, terminal deletion, etc.)” [Spranger, 19781. 21. Community syndrome-“Grouping of conditions of different causes on the basis of clusters of similar manifestations [Spranger, 19781.
McKusick [1974], Gorlin et al. [1976], and Cohen [1976] identify several methods that are used to name
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syndromes: eponyms, geographical designations, signifOther types of false diploeponyms are created when icant clinical features, acronyms, numerical designa- the first and second names are used in single eponyms. tions, names of the earliest patient seen, and etiological An abnormal response of the pupil to light was origicharacteristics. Names of institutions, x-ray charac- nally reported by Douglas Moray Cooper Argyll teristics, and borrowed foreign words are some addi- Robertson and was subsequently named the Robertson tional approaches. As it is now used, syndrome may be syndrome. Some authors, however, prefer the name appended to names of organs and systems, symptoms, Argyll Robertson syndrome, thus creating a false dippathological conditions, and behavioral, social andphys- loeponym. The problem is compounded by overzealous ical phenomena (normal or abnormal), just about any editors who occasionally insert a n inappropriate hyword in the dictionary is a potential candidate for a phen into the eponym (Argyll-Robertson syndrome).The use of first and second names in eponyms has some valid syndrome designation. Most syndromes are eponymous (from Greek epi- reasons, however, as when differentiating syndromes upon, after, and onyma name); i.e., they are named after attributed to David W. Smith from those named after persons or other proper names, such as those of physi- Carl, F.M., Lucian, and other Smiths. The Gilles de la Tourette syndrome may be found in cians, patients, literary, mythological or biblical characters, famous personalities, geographical locations, insti- the literature as de la Tourette syndrome, la Tourette tutions, and even subjects of famous paintings. syndrome, or Tourette syndrome. A few years ago, a syndrome of a genetically transmitTraditionally, most syndromes were named after physicians thought to be the first to have described them. But ted form of slender bone dwarfism would have been as the body of knowledge about a particular syndrome named the Miller-McKusick-Maluau syndrome. But grew, names of other persons who described the condi- now, since the custom of naming syndromes after physition independently (sometimes even earlier than the cians is actively discouraged, i t is called the 3M or MMM presumed original report) were added, thus forming ad- syndrome. The name is unusual in that a n acronym of ditional eponymous designations and multiple epon- this type is usually reserved for syndromes named after yms. A syndrome of macroglossia, omphalocele, and vis- the original patient or salient clinical characteristics of ceromegaly, for instance, was reported independently by the disorder. Also unusual is the name Lou Gehrig disease (amBeckwith in the United States and Wiedemann in Germany. Initially, the syndrome was named both the Beck- yotrophic lateral sclerosis named after a well-known with syndrome and the Wiedemann syndrome. Eventu- baseball player who died of the disease). The eponym, ally, after it was established that these were 2 different although frequently used in the popular press, is pracnames for the same entity, the names were combined tically never seen in the medical literature. Some physicians use eponymous designations as a into a single hyphenated double eponym, the BeckwithWiedemann syndrome in the United States or Wied- device to pay tribute to those whom they admire. For example, Sister Mary Joseph nodule, named by Dr. Willemann-Beckwith syndrome in Europe. Only the names of senior authors of multiauthored iam Mayo in honor of his assistant, and Hedblom synpapers were traditionally used in naming syndromes, drome, named by Dr. M. Joannides in honor of Professor but there have been exceptions. A syndrome of pulmo- Carl A. Hedblom. A fairly recent development in naming syndromes is nary and other disorders associated with the presence of antibodies against cow’s milk was named the Heiner the practice of prefixing the names of well-known synsyndrome even though i t was reported jointly by Heiner dromes with the prefix pseudo-. We thus have pseudoand Sears. The Steuens-Johnson syndrome, on the other Cushing syndrome, pseudo-Hurler syndrome, pseudohand, includes the names of both the senior and junior Sjogren syndrome, and the like, for conditions which are similar to the eponymous syndromes in manifestations, authors of the original report. The term false diploeponym was coined by Shapiro but have different causes, and thus are completely unre[19581,for eponymous designations made up of hyphen- lated to them. There are a large number of new syndromes which are ated surnames. Albers-Schonberg syndrome is a false diploeponym in that it creates the erroneous impression named after patients. Some eponyms include patients’ of being a multiple eponym named after 2 individuals, surnames, a s in Hartnup syndrome (pellagra, cerebellar one named Albers and the other Schonberg. In fact, it is ataxia, and renal aminoaciduria); others are made up of a single eponym named after the German physician, abbreviated names, as in Johnie McL disease (mucopolysaccharidosis I-H); and still others consist of the Heinrich Ernst Albers-Schonberg. Hyphenated author names present still another type first letters of patients’ surnames, such as G syndrome of problem. A syndrome reported jointly by Anton Jer- (hypospadias and dysphagia), or BBB syndrome (hypervell and Fred Lange-Nielsen (sensory deafness associ- telorism associated with hypospadias). The traditional possessive form used for naming eponated with syncope and abnormal ECG), if written conventionally (Jeruell-Lunge-Nielsen syndrome), would yms is now in the process of being replaced by the nomilead one to believe that there are 3 rather than 2 names native form (e.g., “Down syndrome,” instead of “Down’s in the eponym. Leiber and Olbrich [1957] solved the syndrome”). The use of eponymous designations in medicine came problem by inserting a n equal sign ( =) in the double name (Jeruell-Lunge = Nielsen syndrome)and Jablonski under severe scrutiny after World War 11. The Interna[1969,19901,by substituting the hyphen between the 2 tional Nomenclature Committee, appointed by the Fifth names by a n “and” (Jervell and Lunge-Nielsen syn- International Congress in Paris in July 1955, recommended complete elimination of eponyms from the offdrome).
Syndrome cia1 thesaurus of anatomical terms, Nomina Anatomica [19561. Banishment of proper names from the official anatomical vocabulary was followed by a series of papers reexamining the usefulness of eponyms in naming syndromes. Some of the arguments against the use of eponyms include a n accumulation of excessively large numbers of eponyms under some names (more than 10 syndromes were credited to Fanconi) [Jablonski, 19691; difficulty in differentiating syndromes named after different individuals with the same surnames; unfairness in immortalizing some lesser personalities, whereas other more prominent ones were ignored in eponymous designations; obsolescence of eponyms and a contention that more accurate and expressive terminology is available and preferable; confusion created by some eponyms (was Milkman syndrome named after a physician or a milk delivery man?); sometimes erroneous and incomplete information provided in papers whose authors’ names were used in eponymous designations; and false impressions conveyed that some eponyms were given the names of authors originally describing particular syndromes whereas many earlier and better descriptions existed in the literature [Dorgeloh, 1954, 1966; Organ and Sojka, 1961; Ravitch, 19681. On the other hand, there were also those who recognized the usefulness of eponyms [Stiff-man syndrome, 1967; Half-life of eponyms, 1970; McKusick, 19741. Gall’s survey [Gall, 19601 showed that the anti-eponym sentiment was not universal; there were more physicians who approved of eponyms than those who did not. The anti-eponym campaign produced nevertheless a dramatic reduction in the number of syndromes named after physicians. Whereas nearly all new syndromes reported during the first half of the 20th century had a t least one eponymous designation that included the name of a physician, a majority of those reported since the 1960s have been named by other methods. Rising in popularity are eponyms named after mythological, biblical, and literary characters. Thus, we have the Diogenes syndrome (gross neglect, lack of self-consciousness, untidiness, and hoarding of rubbish), Job syndrome (hyperglobulinemia E associated with recurrent staphylococcal abscesses), Munchausen syndrome’ ( a factitious disorder in which the affected person wanders from hospital to hospital and gives accounts of imaginary illnesses), and Munchausen-by-proxy syndrome (a condition in which one person fabricates symptoms for another). The trend now even extends to the use of characters from famous paintings when describing some enigmatic conditions, such as a disorder marked by facial muscle contracture following Bell’s palsy, the Mona Lisa syndrome. Eponymous syndromes named after geographical locations and institutions include Tangier disease (absence or deficiency of high-density lipoprotein), which is named after Tangier Island where it was first observed;
‘The name was anglicized by Raspe in his book, The Adventures of Baron Munchuusen, based on stories of Baron Karl Friedreich von Munchhausen, a German soldier and raconteur.
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Tel Hashomer camptodactyly syndrome (camptodactyly associated with characteristic facies, muscle hypoplasia, skeletal dysplasia, and abnormal palmar creases, which was first reported in Tel Hashomer Hospital in Israel; and Floating Harbor syndrome (growth retardation, delayed speech, aphasia, pseudoarthrosislike anomaly of the clavicle, and other defects), named after the Boston Floating Harbor General Hospital, the site of the first reported case. During the present “post-eponym” period, most authors when naming newly observed syndromes, directed their effort at creating designations that a t least in part reflect the nature of the syndrome and be self-explanatory. They usually include in the names a s much information as possible about major features of the disorder, such a s the names of the organ or organs involved, the phenotype, etiology, genetic characteristics, underlying metabolic defects, or the patient’s physical appearance. The clinical characteristics and the names of organs are the most frequently used elements in formulating syndrome designations. Some syndrome names consist of simple strings of the names of disorders making up the syndrome (hemihypertrophy-semiparesthesia-hemiareflexia syndrome) (also known as hemi-3 syndrome); many identify only the names of involved organs (carpal tunnel syndrome, limb-girdle syndrome, cerebro-arthro-digital syndrome);and others include the names of organs as well as conditions (cerebro-ocular dysplasia-muscular dystrophy syndrome). Occasionally, authors apparently give up the idea of providing a n appropriate term and use instead a descriptive phrase (osteoepiphyseal osteodystrophy of the 0s calcis syndrome). There are certain syndromes which are too complex and contain too many significant elements to fit into a simple string of terms. In these instances, they are designated by acronyms. Thus, the LEOPARD syndrome) (lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, sensorineural deafness), and REST syndrome (Raynaud phenomenon, esophageal motor dysfunction, sclerodactyly, telangiectasia). Other approaches used in naming syndromes include: etiological factors (overuse syndrome, crush syndrome); teratogenic factors (thalidomide syndrome, fetal hydantoin syndrome); occupational factors (sick building syndrome);underlying biochemical defects (glycogen storage disease or syndrome); underlying enzymatic defects (branched chain alpha-keto acid dehydrogenase syndrome);malfunctioning appliances (respirator lung syndrome, pacemaker syndrome); and ECG abnormalities (long QT syndrome). Increasing in popularity are borrowed foreign words or expressions to name syndromes, such as: Latah syndrome (exaggerated startle reaction observed in Malaysia and Indonesia); moyamoya syndrome (cloudiness seen on the angiographic picture in obliteration of the intracranial carotid arteries; moyamoya in Japanese means something hazy, like a puff of smoke); cri d u chat syndrome (a peculiar sound made by the infant, resembling that of a crying kitten; the French cri du chat means crying cat); mort d’amour syndrome (fatal car-
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diac arrhythmia during sexual intercourse; in F’rench, mort d’amour means dying of love). And there is an additional vast array of more or less imaginative syndrome designations; jumping Frenchman of Maine syndrome (exaggerated startle reaction); Sunday syndrome (periodic amphetamine abuse by football players); sundown syndrome (confusion and restlessness in elderly persons at sunset); sunrise syndrome (subluxation of the intraocular lens);travellers’ diarrhea syndrome, UFO syndrome, oh my aching back syndrome (not to be confused with oh my aching feet syndrome), and so forth. Once a convenient designation used to identify those conditions which are characterized by defined clusters of recurring manifestations (such as multiple malformations), the term syndrome has come to be used by many writers randomly, merely to accentuate the complexity of any disorder, or even to be amusing, thus compromising the term. One of the immediate consequences of this uncontrolled use of the term is a n enormous increase in the volume of syndrome literature, which, in turn, causes problems in the identification of specific syndromes in medical data bases, such as MEDLARS. The problem of storage and retrieval of syndrome literature will be discussed in a subsequent article.
ACKNOWLEDGMENTS I would like to express my thanks for their comments and suggestions to Drs. John M. Opitz, Robert J. Gorlin, Jurgen W. Spranger, and Hans Rudolf Wiedemann. I would also like to acknowledge the generous and expert cooperation of members of the staff of the Index Section and Reference Services of the National Library of Medicine, particularly Dr. Maria Farkas, Karen Patrias, Loretta Ulincy, Mary Hantzes, Thelma Charen, and Lillian Scanlon. REFERENCES Beighton P, Beighton G (1986): “The Man Behind the Syndrome.” Berlin: Springer, 240 p. Billings J S (1890):The National Medical Dictionary. Philadelphia: Lea Brothers. Burg G, Kunze J, Pongratz D, Scheurlen PG, Schinzel A, Spranger J (1990):“Leiber. Klinischen Syndrome, Syndrome, Sequenzen und Symptomtemenkomplexe.”7th Ed. Miinchen: Urban & Schwarzenberg. Castelli B (1755):“Lexicon Medicorum Graeco-Latinum.” Patavium: J . Manfre. Cohen MM J r (1976): Syndrome designations. J Med Genet 13:266-270. Dorgeloh J (October 1954): Murphy is a drip. Med Econ pp 153-156. Dorgeloh J (October 1966): Milkman’s syndrome. Do you mean Dr. Milkman? Med Econ pp 194-195. Dorland W (1900):“The American Medical Dictionary.” 1st Ed. Philadelphia: Saunders.
“Dorlands Illustrated Medical Dictionary” (1988). 27th Ed. Philadelphia: Saunders. English HP, English AC (1958):“A Comprehensive Dictionary of Psychological and Psychoanalytical Terms.” New York: McKay. Gall EA (Mar 1960): The medical eponym. Am Scientist pp 51-57. Gorlin R J , Pindborg JJ, Cohen MM J r (1976):“Syndromes of the Head and Neck.” 2nd Ed. New York: McGraw-Hill. Giinther H (1948-1949): Anomaliekomplex und Zafallssyndromie. Zentralbl Allg Pathol pp 6-16. Half-life of eponyms (editorial) (1970): JAMA 21:456. Hirschhorn K (1981): New syndromes and modern genetics. N Engl J Med 305638-639. Jablonski S (1969): “Illustrated Dictionary of Eponymic Syndromes and their Synonyms.” Philadelphia: Saunders. Jablonski S (1990):“Dictionary of Syndromes and Eponymic Diseases.” Melbourne, FL: Krieger. Leiber B, Olbrich G (1957): “Die Klinischen Syndrome.” 1st Ed. Miinchen: Urbach & Schwarzenberg. McKusick VA (1974): Nomenclature of syndromes. BD:OAS X(7): 61-86. Motherby G (1801): “A New Medical Dictionary of General Repository of Physics.” 5th Ed. Revised by G. Wallis. London: J. Johnson. Murray JA, Bradley N, Craigie WA, Onions CT (1919):“English Dictionary on Historical Principles.” Oxford: Clarendon Press. Nomina Anatomica (1956): Baltimore, Williams & Wilkins. Opitz JM, Czeizel A, Evans JA, Hall JG, Lubinsky MS, Spranger JW (1987): Nosologic grouping in birth defects. In Vogel F, Sperling K (eds): “Human Genetics.” Proceedings of ‘7th International Congress, Berlin, 1986. Opitz JM, Herrmann J , Pettersen JC, Bersu ET, Colacino SC (1979): Terminological, diagnostic, nosological, and anatomical-developmental aspects of developmental defects in man. Adv Hum Genet 9:71-164. Organ CH J r , Sojka LA (1961): The eponym problem. Am J Surg 101:l-2. Pfaundler M, von Seht L (1922): Uber Syntropie von Krankheitszustanden. Z Kinderh 3O:lOO-120. Pinsky L (1977): The polythetic (phenotypic community) system of classifying malformation syndromes. BD:OAS XIII(3A):13-30. Ravitch MM (1968): Eponyms. Med Times 11:49-51. Shapiro E (1958): The development and meaning of the hyphenated eponym in medical history. Arch Intern Med 101:662-668. Smith DW (1974): Nomenclature of syndromes. BD:OAS X(7):65-67. Smith MJ (1965): On the nature and terminology ofsyndromes, particularly of the gastrointestinal tract. Rocky Mount Med J 62(4): 34-39, 49. Spranger JW (November 30-December, 1978): Developmental t e r m s s o m e proposals. First report of an International Working Group, Mainz. Spranger JW: Personal communication. Spranger J W (1989): Krankheit, Syndrom, Sequenz. Monatsschr Kinderheilkd 137:2-7. Spranger J , Benirschke K, Hall JG, Lenz W, Lowry RB, Opitz JM, Pinsky L, Schwarzacher HG, Smith DW (1982): Errors in morphogenesis. Concepts and terms. %commendations of an International Working Group. J Pediatr 100:160-165. Stiff-man syndrome (editorial) (1967): JAMA 201:321. Warkany J (1974): Overview of malformation syndromes. BDOAS X(7):1-5.
Syndrome: Le Mot de Jour Stanley Jablonski
Syndrome is one of the oldest terms in the medical vocabulary. It has been used as a designation for those disorders that were marked by etiologically nonspecific similar groups of manifestations up to the time of Sydenham. His contention that the terms syndrome and disease were in fact synonymous explains in part infrequent use of syndrome in the literature until the latter part of the 19th century. Redefinition of syndrome early in the 20th century as a disorder characterized by the concurrence of symptoms which are causally related, and further refinement of the definition as a condition marked by a cluster of symptoms occurring together coincidentally, gradually restored the popularity of the term to where syndrome is now one of the most frequently used designations of morbid states in the literature. There are numerous definitions of syndrome currently in use. One which is accepted by most dysmorphologists, geneticists, and some clinicians states that syndrome is an etiologically defined entity of unknown pathogenesis. However, most writers use the term randomly to denote any abnormal condition, whether medical, social, or behavioral, when a more satisfactory designation cannot be found or created, or to emphasize special complexity (syndromic qualities?) of already named diseases, or merely to be amusing. The post-Sydenham custom of naming of syndromes after physicians gave way in the mid-20th century to methods wherein syndrome names incorporate clinical, etiological, genetic, and other significant characteristics. Other methods used in designating syndromes include using the names of the first patient known to be affected, acronyms and abbreviations, personal names of all kinds, and the like. Syndrome, once a unique and valuable term in the
arsenal of medical vocabulary, has lost much of its usefulness through misuse.
KEY WORDS: syndrome, history, terminology
The word syndrome (from Greek syn together and d r h o s a course [Latin concursusl) means concurrence; things running together. It is one of the oldest terms in the medical vocabulary, and said to have been used by Hippocrates and Galen [Castelli, 1775; Murray et al., 19191. A definition in Motherby’s dictionary [I8611 (an adaptation from Castelli’s Lexicon Medicorum GraecoLatinum, describes syndrome as a term which was . . introduced by the sect of empiric physicians to express the concourse of congeries of symptoms: for instance, the concourse of symptoms when diseases arise from plethora, are called plethoric syndrome. So may there be a cacochymic syndrome; and indeed it may apply less generally, as a choleric, phlegmatic, pleuritic, epileptic syndrome &c.” By the end of the 19th century, definitions became more to the point. In his dictionary, Billings [18901, defined the term as “a name denoting the aggregate of symptoms of disease,” and Dorland [19001 defined it a s a “complex of symptoms; a set of symptoms that occur together; a sum of signs of any morbid state.” Dorland‘s definition, although somewhat modified is still used in most medical dictionaries. Through the 19th and the first half of the 20th centuries, the term syndrome was used in the medical literature to name disorders characterized by multiple symptoms with a tendency to occur together, and involved various, sometimes apparently unrelated, organs and systems, which frequently occurred without any immediately explainable cause. That is, disorders which baffled physicians and, in spite of their considerable linguistic skills, defied their ability to coin appropriate terms by means of combining word fragments into a single designation, as would have been possible with other, less complex, conditions. Whenever enough was known about a disorder, the available information would Received for publication May 9, 1990; revision received October have been incorporated into the term which was then appended by syndrome. Otherwise, the syndrome was 10, 1990. named after the physician believed to have originally Address reprint requests to Stanley Jablonski, 8603 Virginia described it. Thomas Sydenham’s redefinition of the Avenue, Annandale, VA 22003. S.Jablonski was formerly with the National Library of Medicine term disease represents a n early, although indirect, attempt at restricting the meaning of the term syndrome. in Bethesda, Maryland.
0 1991 Wiley-Liss, Inc.
‘I.
Syndrome Before Sydenham, disease denoted the subjective state of a n ill person, whereas syndrome referred to the signs and symptoms listed by the physician. According to Syndenham’s definition, both terms are synonymous, thus rendering syndrome superfluous and, in part, explaining its relative infrequent use until the latter part of the 19th century [Spranger, 19891. The scope of the definition of syndrome was further narrowed in 1921by Pfaundler and von Seht [1922], who coined the term syntropy (from Greek syn together, with, tropos a turning; turning toward each other) to encompass those disorders which are characterized by the concurrence of symptoms that are causally related; thus dividing syndromes into those which are marked by symptoms which have a common cause and those which do not. This refinement was further advanced by Gunther [1948], who defined syndrome as a disorder that is marked by a cluster of symptoms occurring together coincidentally; not to be confused with symptom complex, which is a manifestation of disease, the symptoms being caused by the underlying disease. Gunther used the occasion to deplore the deterioration of scholarship in medicine, pointing out that the Greek feminine noun syndrome is incorrectly translated into modern languages, such as le syndrome (masculine noun) in French and das Syndrom (a neuter noun) in German. His suggestion t h a t the German Syndrom should be replaced by the more appropriate die Syndromie (English syndromy) never gained popular acceptance. There are numerous, sometimes conflicting, definitions of the term syndrome now in use. 1. A set of symptoms which occur together; the sum of signs of any morbid state; a symptom complex. In genetics, a pattern of multiple malformations [Dorland’s Illustrated Medical Dictionary, 19881. 2. In general medicine, syndrome is synonymous with symptom complex [Warkany, 19741. 3. A constant unhealthy coexistence of abnormal symptoms and signs whose relationships to underlying disorders are obscure [Smith, 19651. 4. Apparently specific clinical disorder of multiple defects. If and when the more basic etiology has been clarified, then the disorder might be considered a specific disease entity [Smith, 19741. 5. (a)The pattern of symptoms that characterizes a particular disorder or disease. . . ; (b) loosely, a cluster of characteristics; a set of behaviors believed to have a common cause or basis [English and English, 19581. 6. A congenital syndrome is generally considered to be: constellation of abnormalities due to a single developmental or genetic defect [Hirschhorn, 19811. 7. . . . a n etiologically defined entity of unknown pathogenesis [Spranger, 19891. (Not to be confused with disease, symptom complex, or sequence.) Further attempts to standardize the meaning of syndrome resulted in additional terms and definitions. 8. Syndrome definition-“The elucidation the cause of syndrome” [Spranger, 19891. 9. Syndrome delineation-“The study of the phenotype and natural history of the syndrome” [Opitz et al., 19791.
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10. Causal (true) syndromy [syndrome]-“. . . a causally defined pleiotropic disorder” [Opitz et al., 19791. 11. False syndromy [syndrome]--“ . . . includes coincidental and associational syndromy, i.e., types of syndromy that do not represent pleiotropy or other developmentally and/or functionally correlated manifestations of a single cause such a s mendelian mutation, chromosome abnormality, or teratogenic agents” [Opitz et al., 19791. 12. Assocational syndromy [syndrome] or association-“ . . . a variety of false syndromy in which two or more manifestations in the patient (or his family or both) represent noncausal concurrence, due either to linkage or to a linkage-disequilibrium situation” [Opitz et al., 19791. 13. “ . . . a nonrandom association of defects which cannot be interpreted as the consequence of a single primary localized defect in morphogenesis or delineation as a specific syndrome or disease in terms of the total clinical findings and etiology” [Smith, 19791. 14. Hippocratic (symptomatic) syndromy [syndrome]-“ . . . refers to patients with etiologically nonspecific similar or identical sets of manifestations . . . It is presumed that the several manifestations or symptoms of the patients are due to a single cause that varies from patient to patient, though their conditions may be very similar. . . that seems to have the original use of the term from Hippocrates through Galen to the days of Sydenham” [Opitz et al., 19791. 15. Formal genesis syndromy [syndrome]-One that is pathogenically defined [Opitz et al., 19791. 16. Causal genesis syndromy [syndrome]-“Initially the use of this was restricted to multiple manifestations (mostly structural) of mendelian mutation . . . we think it is quite appropriate to extend the use ofthe term to the multiple developmental manifestations of chromosome mutation as well, while keeping in mind that their effect is or may be produced in a developmentally different manner than in the case of, say a complex autosomal recessive t r a i t . . . ” [Opitz et al., 19793. 17. Physical examination syndrome-“The patient in whom the first particular combination of physical manifestations has been observed can be said to have physical examination syndrome” [Opitz et al., 19791. 18. Private syndrome-“A malformation syndrome due to a n apparently unique chromosome rearrangement which may or may not segregate in a family” [McKusick, 19741. 19. Provisionally private syndrome--“ . . . refers to two or more sibs with the same malformation syndrome, nonconsanguineous parents, and with apparently normal karyotype in patients and parents” [McKusick, 19741. 20. Public syndrome--“A malformation syndrome due to chromosomal abnormalities which recur with a specific frequency in the population (e.g., trisomy, centric fusion, terminal deletion, etc.)” [Spranger, 19781. 21. Community syndrome-“Grouping of conditions of different causes on the basis of clusters of similar manifestations [Spranger, 19781.
McKusick [1974], Gorlin et al. [1976], and Cohen [1976] identify several methods that are used to name
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syndromes: eponyms, geographical designations, signifOther types of false diploeponyms are created when icant clinical features, acronyms, numerical designa- the first and second names are used in single eponyms. tions, names of the earliest patient seen, and etiological An abnormal response of the pupil to light was origicharacteristics. Names of institutions, x-ray charac- nally reported by Douglas Moray Cooper Argyll teristics, and borrowed foreign words are some addi- Robertson and was subsequently named the Robertson tional approaches. As it is now used, syndrome may be syndrome. Some authors, however, prefer the name appended to names of organs and systems, symptoms, Argyll Robertson syndrome, thus creating a false dippathological conditions, and behavioral, social andphys- loeponym. The problem is compounded by overzealous ical phenomena (normal or abnormal), just about any editors who occasionally insert a n inappropriate hyword in the dictionary is a potential candidate for a phen into the eponym (Argyll-Robertson syndrome).The use of first and second names in eponyms has some valid syndrome designation. Most syndromes are eponymous (from Greek epi- reasons, however, as when differentiating syndromes upon, after, and onyma name); i.e., they are named after attributed to David W. Smith from those named after persons or other proper names, such as those of physi- Carl, F.M., Lucian, and other Smiths. The Gilles de la Tourette syndrome may be found in cians, patients, literary, mythological or biblical characters, famous personalities, geographical locations, insti- the literature as de la Tourette syndrome, la Tourette tutions, and even subjects of famous paintings. syndrome, or Tourette syndrome. A few years ago, a syndrome of a genetically transmitTraditionally, most syndromes were named after physicians thought to be the first to have described them. But ted form of slender bone dwarfism would have been as the body of knowledge about a particular syndrome named the Miller-McKusick-Maluau syndrome. But grew, names of other persons who described the condi- now, since the custom of naming syndromes after physition independently (sometimes even earlier than the cians is actively discouraged, i t is called the 3M or MMM presumed original report) were added, thus forming ad- syndrome. The name is unusual in that a n acronym of ditional eponymous designations and multiple epon- this type is usually reserved for syndromes named after yms. A syndrome of macroglossia, omphalocele, and vis- the original patient or salient clinical characteristics of ceromegaly, for instance, was reported independently by the disorder. Also unusual is the name Lou Gehrig disease (amBeckwith in the United States and Wiedemann in Germany. Initially, the syndrome was named both the Beck- yotrophic lateral sclerosis named after a well-known with syndrome and the Wiedemann syndrome. Eventu- baseball player who died of the disease). The eponym, ally, after it was established that these were 2 different although frequently used in the popular press, is pracnames for the same entity, the names were combined tically never seen in the medical literature. Some physicians use eponymous designations as a into a single hyphenated double eponym, the BeckwithWiedemann syndrome in the United States or Wied- device to pay tribute to those whom they admire. For example, Sister Mary Joseph nodule, named by Dr. Willemann-Beckwith syndrome in Europe. Only the names of senior authors of multiauthored iam Mayo in honor of his assistant, and Hedblom synpapers were traditionally used in naming syndromes, drome, named by Dr. M. Joannides in honor of Professor but there have been exceptions. A syndrome of pulmo- Carl A. Hedblom. A fairly recent development in naming syndromes is nary and other disorders associated with the presence of antibodies against cow’s milk was named the Heiner the practice of prefixing the names of well-known synsyndrome even though i t was reported jointly by Heiner dromes with the prefix pseudo-. We thus have pseudoand Sears. The Steuens-Johnson syndrome, on the other Cushing syndrome, pseudo-Hurler syndrome, pseudohand, includes the names of both the senior and junior Sjogren syndrome, and the like, for conditions which are similar to the eponymous syndromes in manifestations, authors of the original report. The term false diploeponym was coined by Shapiro but have different causes, and thus are completely unre[19581,for eponymous designations made up of hyphen- lated to them. There are a large number of new syndromes which are ated surnames. Albers-Schonberg syndrome is a false diploeponym in that it creates the erroneous impression named after patients. Some eponyms include patients’ of being a multiple eponym named after 2 individuals, surnames, a s in Hartnup syndrome (pellagra, cerebellar one named Albers and the other Schonberg. In fact, it is ataxia, and renal aminoaciduria); others are made up of a single eponym named after the German physician, abbreviated names, as in Johnie McL disease (mucopolysaccharidosis I-H); and still others consist of the Heinrich Ernst Albers-Schonberg. Hyphenated author names present still another type first letters of patients’ surnames, such as G syndrome of problem. A syndrome reported jointly by Anton Jer- (hypospadias and dysphagia), or BBB syndrome (hypervell and Fred Lange-Nielsen (sensory deafness associ- telorism associated with hypospadias). The traditional possessive form used for naming eponated with syncope and abnormal ECG), if written conventionally (Jeruell-Lunge-Nielsen syndrome), would yms is now in the process of being replaced by the nomilead one to believe that there are 3 rather than 2 names native form (e.g., “Down syndrome,” instead of “Down’s in the eponym. Leiber and Olbrich [1957] solved the syndrome”). The use of eponymous designations in medicine came problem by inserting a n equal sign ( =) in the double name (Jeruell-Lunge = Nielsen syndrome)and Jablonski under severe scrutiny after World War 11. The Interna[1969,19901,by substituting the hyphen between the 2 tional Nomenclature Committee, appointed by the Fifth names by a n “and” (Jervell and Lunge-Nielsen syn- International Congress in Paris in July 1955, recommended complete elimination of eponyms from the offdrome).
Syndrome cia1 thesaurus of anatomical terms, Nomina Anatomica [19561. Banishment of proper names from the official anatomical vocabulary was followed by a series of papers reexamining the usefulness of eponyms in naming syndromes. Some of the arguments against the use of eponyms include a n accumulation of excessively large numbers of eponyms under some names (more than 10 syndromes were credited to Fanconi) [Jablonski, 19691; difficulty in differentiating syndromes named after different individuals with the same surnames; unfairness in immortalizing some lesser personalities, whereas other more prominent ones were ignored in eponymous designations; obsolescence of eponyms and a contention that more accurate and expressive terminology is available and preferable; confusion created by some eponyms (was Milkman syndrome named after a physician or a milk delivery man?); sometimes erroneous and incomplete information provided in papers whose authors’ names were used in eponymous designations; and false impressions conveyed that some eponyms were given the names of authors originally describing particular syndromes whereas many earlier and better descriptions existed in the literature [Dorgeloh, 1954, 1966; Organ and Sojka, 1961; Ravitch, 19681. On the other hand, there were also those who recognized the usefulness of eponyms [Stiff-man syndrome, 1967; Half-life of eponyms, 1970; McKusick, 19741. Gall’s survey [Gall, 19601 showed that the anti-eponym sentiment was not universal; there were more physicians who approved of eponyms than those who did not. The anti-eponym campaign produced nevertheless a dramatic reduction in the number of syndromes named after physicians. Whereas nearly all new syndromes reported during the first half of the 20th century had a t least one eponymous designation that included the name of a physician, a majority of those reported since the 1960s have been named by other methods. Rising in popularity are eponyms named after mythological, biblical, and literary characters. Thus, we have the Diogenes syndrome (gross neglect, lack of self-consciousness, untidiness, and hoarding of rubbish), Job syndrome (hyperglobulinemia E associated with recurrent staphylococcal abscesses), Munchausen syndrome’ ( a factitious disorder in which the affected person wanders from hospital to hospital and gives accounts of imaginary illnesses), and Munchausen-by-proxy syndrome (a condition in which one person fabricates symptoms for another). The trend now even extends to the use of characters from famous paintings when describing some enigmatic conditions, such as a disorder marked by facial muscle contracture following Bell’s palsy, the Mona Lisa syndrome. Eponymous syndromes named after geographical locations and institutions include Tangier disease (absence or deficiency of high-density lipoprotein), which is named after Tangier Island where it was first observed;
‘The name was anglicized by Raspe in his book, The Adventures of Baron Munchuusen, based on stories of Baron Karl Friedreich von Munchhausen, a German soldier and raconteur.
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Tel Hashomer camptodactyly syndrome (camptodactyly associated with characteristic facies, muscle hypoplasia, skeletal dysplasia, and abnormal palmar creases, which was first reported in Tel Hashomer Hospital in Israel; and Floating Harbor syndrome (growth retardation, delayed speech, aphasia, pseudoarthrosislike anomaly of the clavicle, and other defects), named after the Boston Floating Harbor General Hospital, the site of the first reported case. During the present “post-eponym” period, most authors when naming newly observed syndromes, directed their effort at creating designations that a t least in part reflect the nature of the syndrome and be self-explanatory. They usually include in the names a s much information as possible about major features of the disorder, such a s the names of the organ or organs involved, the phenotype, etiology, genetic characteristics, underlying metabolic defects, or the patient’s physical appearance. The clinical characteristics and the names of organs are the most frequently used elements in formulating syndrome designations. Some syndrome names consist of simple strings of the names of disorders making up the syndrome (hemihypertrophy-semiparesthesia-hemiareflexia syndrome) (also known as hemi-3 syndrome); many identify only the names of involved organs (carpal tunnel syndrome, limb-girdle syndrome, cerebro-arthro-digital syndrome);and others include the names of organs as well as conditions (cerebro-ocular dysplasia-muscular dystrophy syndrome). Occasionally, authors apparently give up the idea of providing a n appropriate term and use instead a descriptive phrase (osteoepiphyseal osteodystrophy of the 0s calcis syndrome). There are certain syndromes which are too complex and contain too many significant elements to fit into a simple string of terms. In these instances, they are designated by acronyms. Thus, the LEOPARD syndrome) (lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, sensorineural deafness), and REST syndrome (Raynaud phenomenon, esophageal motor dysfunction, sclerodactyly, telangiectasia). Other approaches used in naming syndromes include: etiological factors (overuse syndrome, crush syndrome); teratogenic factors (thalidomide syndrome, fetal hydantoin syndrome); occupational factors (sick building syndrome);underlying biochemical defects (glycogen storage disease or syndrome); underlying enzymatic defects (branched chain alpha-keto acid dehydrogenase syndrome);malfunctioning appliances (respirator lung syndrome, pacemaker syndrome); and ECG abnormalities (long QT syndrome). Increasing in popularity are borrowed foreign words or expressions to name syndromes, such as: Latah syndrome (exaggerated startle reaction observed in Malaysia and Indonesia); moyamoya syndrome (cloudiness seen on the angiographic picture in obliteration of the intracranial carotid arteries; moyamoya in Japanese means something hazy, like a puff of smoke); cri d u chat syndrome (a peculiar sound made by the infant, resembling that of a crying kitten; the French cri du chat means crying cat); mort d’amour syndrome (fatal car-
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diac arrhythmia during sexual intercourse; in F’rench, mort d’amour means dying of love). And there is an additional vast array of more or less imaginative syndrome designations; jumping Frenchman of Maine syndrome (exaggerated startle reaction); Sunday syndrome (periodic amphetamine abuse by football players); sundown syndrome (confusion and restlessness in elderly persons at sunset); sunrise syndrome (subluxation of the intraocular lens);travellers’ diarrhea syndrome, UFO syndrome, oh my aching back syndrome (not to be confused with oh my aching feet syndrome), and so forth. Once a convenient designation used to identify those conditions which are characterized by defined clusters of recurring manifestations (such as multiple malformations), the term syndrome has come to be used by many writers randomly, merely to accentuate the complexity of any disorder, or even to be amusing, thus compromising the term. One of the immediate consequences of this uncontrolled use of the term is a n enormous increase in the volume of syndrome literature, which, in turn, causes problems in the identification of specific syndromes in medical data bases, such as MEDLARS. The problem of storage and retrieval of syndrome literature will be discussed in a subsequent article.
ACKNOWLEDGMENTS I would like to express my thanks for their comments and suggestions to Drs. John M. Opitz, Robert J. Gorlin, Jurgen W. Spranger, and Hans Rudolf Wiedemann. I would also like to acknowledge the generous and expert cooperation of members of the staff of the Index Section and Reference Services of the National Library of Medicine, particularly Dr. Maria Farkas, Karen Patrias, Loretta Ulincy, Mary Hantzes, Thelma Charen, and Lillian Scanlon. REFERENCES Beighton P, Beighton G (1986): “The Man Behind the Syndrome.” Berlin: Springer, 240 p. Billings J S (1890):The National Medical Dictionary. Philadelphia: Lea Brothers. Burg G, Kunze J, Pongratz D, Scheurlen PG, Schinzel A, Spranger J (1990):“Leiber. Klinischen Syndrome, Syndrome, Sequenzen und Symptomtemenkomplexe.”7th Ed. Miinchen: Urban & Schwarzenberg. Castelli B (1755):“Lexicon Medicorum Graeco-Latinum.” Patavium: J . Manfre. Cohen MM J r (1976): Syndrome designations. J Med Genet 13:266-270. Dorgeloh J (October 1954): Murphy is a drip. Med Econ pp 153-156. Dorgeloh J (October 1966): Milkman’s syndrome. Do you mean Dr. Milkman? Med Econ pp 194-195. Dorland W (1900):“The American Medical Dictionary.” 1st Ed. Philadelphia: Saunders.
“Dorlands Illustrated Medical Dictionary” (1988). 27th Ed. Philadelphia: Saunders. English HP, English AC (1958):“A Comprehensive Dictionary of Psychological and Psychoanalytical Terms.” New York: McKay. Gall EA (Mar 1960): The medical eponym. Am Scientist pp 51-57. Gorlin R J , Pindborg JJ, Cohen MM J r (1976):“Syndromes of the Head and Neck.” 2nd Ed. New York: McGraw-Hill. Giinther H (1948-1949): Anomaliekomplex und Zafallssyndromie. Zentralbl Allg Pathol pp 6-16. Half-life of eponyms (editorial) (1970): JAMA 21:456. Hirschhorn K (1981): New syndromes and modern genetics. N Engl J Med 305638-639. Jablonski S (1969): “Illustrated Dictionary of Eponymic Syndromes and their Synonyms.” Philadelphia: Saunders. Jablonski S (1990):“Dictionary of Syndromes and Eponymic Diseases.” Melbourne, FL: Krieger. Leiber B, Olbrich G (1957): “Die Klinischen Syndrome.” 1st Ed. Miinchen: Urbach & Schwarzenberg. McKusick VA (1974): Nomenclature of syndromes. BD:OAS X(7): 61-86. Motherby G (1801): “A New Medical Dictionary of General Repository of Physics.” 5th Ed. Revised by G. Wallis. London: J. Johnson. Murray JA, Bradley N, Craigie WA, Onions CT (1919):“English Dictionary on Historical Principles.” Oxford: Clarendon Press. Nomina Anatomica (1956): Baltimore, Williams & Wilkins. Opitz JM, Czeizel A, Evans JA, Hall JG, Lubinsky MS, Spranger JW (1987): Nosologic grouping in birth defects. In Vogel F, Sperling K (eds): “Human Genetics.” Proceedings of ‘7th International Congress, Berlin, 1986. Opitz JM, Herrmann J , Pettersen JC, Bersu ET, Colacino SC (1979): Terminological, diagnostic, nosological, and anatomical-developmental aspects of developmental defects in man. Adv Hum Genet 9:71-164. Organ CH J r , Sojka LA (1961): The eponym problem. Am J Surg 101:l-2. Pfaundler M, von Seht L (1922): Uber Syntropie von Krankheitszustanden. Z Kinderh 3O:lOO-120. Pinsky L (1977): The polythetic (phenotypic community) system of classifying malformation syndromes. BD:OAS XIII(3A):13-30. Ravitch MM (1968): Eponyms. Med Times 11:49-51. Shapiro E (1958): The development and meaning of the hyphenated eponym in medical history. Arch Intern Med 101:662-668. Smith DW (1974): Nomenclature of syndromes. BD:OAS X(7):65-67. Smith MJ (1965): On the nature and terminology ofsyndromes, particularly of the gastrointestinal tract. Rocky Mount Med J 62(4): 34-39, 49. Spranger JW (November 30-December, 1978): Developmental t e r m s s o m e proposals. First report of an International Working Group, Mainz. Spranger JW: Personal communication. Spranger J W (1989): Krankheit, Syndrom, Sequenz. Monatsschr Kinderheilkd 137:2-7. Spranger J , Benirschke K, Hall JG, Lenz W, Lowry RB, Opitz JM, Pinsky L, Schwarzacher HG, Smith DW (1982): Errors in morphogenesis. Concepts and terms. %commendations of an International Working Group. J Pediatr 100:160-165. Stiff-man syndrome (editorial) (1967): JAMA 201:321. Warkany J (1974): Overview of malformation syndromes. BDOAS X(7):1-5.
