American Journal of Medical Genetics 41:126-127 (1991)
Editorial Comment
Otto Ullrich: An Appreciation John M. Opitz Department of Medical Genetics, Shodair Children’s Hospital, Helena, Montana In several ways Meinhard von Pfaundler (18721947), one of the greatest German pediatricians (together with Adalbert Czerny) in the first half of this century, has had a remarkable influence on me. His third student to attain a Chairmanship was Rudolf Degkwitz (1889-1973), who was Professor of Pediatrics in Hamburg between 1932 and 1949 [Wiedemann, 19851. After my father’s death of tuberculosis Degkwitz became my pediatrician, diagnosed the same disease in me, and promptly had me bundled off to a sanatorium for 14 months with much rest, good food, fresh air, and regular doses of cod liver oil. Terror struck upon my return to Hamburg to live with my grandfather when it was decided that frequent transfusions of small amounts of fresh blood (directly from the donor) would strengthen my constitution and hasten my recovery. I lived in fear and dread of those weekly subway trips into the University Hospitals Hamburg-Eppendorf (later badly bombed) and was assuaged only by Degkwitz’s kindness in allowing me to play with his guinea pig named Mohrle (little carrot) who lived under the sofa in his waiting room. During those moments of respite, Degkwitz and my grandfather closeted themselves with a precious cigar and sip from a dwindling stock of sherry in his exam room in order (as I learned later) to vent their mutual ire about the present political regime and its catastrophic effect on all aspects of life. Both survived the serious reprisals visited on them by the regime but emigrated in a rage after the war never to return, Degkwitz to the U.S.A. and my grandfather to Cambridge in England. Through von Pfaundler’s fifth student to attain a chairmanship, Otto Ullrich (1894-19571, I have been privileged with the friendship of Ullrich’s student HansRudolf Wiedemann (Chairman in Kiel from 1961-1980) and Wiedemann’s student Jiirgen Spranger who has been Chairman in Mainz since 1974. One of von Pfaundler’s major merits as a scientist was his introduction of mathematical methods into the study of combined or complex manifestations in pediatrics. He invented and successfully applied the syntropy index, the most important intellectual advance in the study of diseases as specific entities since Sydenham and the advent of the germ theory [Faber, 19231. As early as Received for publication March 14,1990; revision received April 27, 1990. Address reprint requests to Dr. John M. Opitz, Shodair Children Hospital, 840 Helena Avenue, P.O. Box 5539, Helena, MT 59604.
0 1991 Wiley-Liss, Inc.
1911von Pfaundler pointed out that concurrent complex disease manifestations may have common cause. With respect to constitutional disorders he later coined the concept of multiple congenital anomalies (MCA) (multiple Abartungen), i.e., a core of malformations around which are grouped with variable frequency, numerous other signs of developmental abnormality. The constancy of the recurrence of the leading or core manifestations confirms the conditions as a discrete entity [Starke, 19501. The MCA concept was developed by Ullrich in three important ways. 1)He recognized that in certain typical MCA combinations (syndromes)family resemblance was abolished. This is now known as one of the most sensitive indicators of the presence of aneuploidy and was first discussed by Ullrich in connection with his delineation of what came to be called later the Ullrich-Turner syndrome. In his classic prototype description [19301he records that the child‘s “appearance still was somewhat odd [and that she] did not have any family resemblance a t all.” 2) He recognized and discussed in the same 1930 paper the similarity of many manifestations shared by the Ullrich-Turner and Down syndromes (e.g., shortness of stature, congenital lymphedema, webbing of the neck, ptosis, and “numerous individual malformations and anomalies of incomplete differentiation in the most diverse of organ systems”),concluding that these two conditions must share a similar pathogenesis “im Beginn der Ontogenese,” i.e., from the very beginning of development, which may be “. . . in der Keimanlage praedetermieniert” (predetermined in the germ cell) . .. durch idiotypische Momente . . . ,” i.e., by genetic causes [in the language of Siemens, 19211. 3) Long before his confrontation with Kristine Bonnevie’s work on the myelencephalic bleb mouse of Bagg and Little, Ullrich clearly outlined the picture of symmetrical congenital lymphedema, which resorbs gradually during the first year or two years of life and is associated with congenital redundancy of the skin at the nape of the neck and later pterygium colli, (facultative) movement disorders with webbing elsewhere, lymphedema of limbs, nail and nipple “dysplasia,” ptosis, other occasional cranial nerve palsies, and aortic coarctation. This is classical work as valid today as it was then. However, in his enthusiasm for the myelencephalic bleb theory he dismissed a bit too lightly the important observation of Griinwald and Kornfeld (1935/6) who reported on a 4-month-old human fetus with severe (cystic hygroma-like) lymphedema of neck,
Editorial Comment shoulders, back, anterior abdominal wall, and parts of arms and legs. They also observed a most conspicuous and extensive system of spongy cavernous spaces extruding from the jugular system into the upper mediastinum, a condition they likened to an arrest of the lymph system at an earlier developmental stage [Ullrich, 19381. It is a particularly appealing aspect of this man’s life that inspite of his genius he was not infallible. Yet most of what he accomplished remains a permanent contribution to our patrimony of developmental pediatrics and genetics. Ullrich’s main strength was in phenotype analysis, i.e., the analysis of the pathogenesis of MCA syndrome from a pediatric and a genetic perspective. In a masterful review on the subject from 1937he clearly stated that variability was due to the environmental and epigenetic factors, discussed the concept of pleiotropy, spoke of the myelencephalic bleb “consequences” in the developing mouse in terms which read like a modern description of a sequence, and emphasized the concept of heterogeneity, namely, that “phenotypically similar-appearing anomalies may arise due to genetically. . . totally different causes.”
EPILOGUE Shortly after the formation of the American Society of Human Genetics, H.J. Muller asked C.W. Cotterman to become editor of the American Journal of Human Genetics. Viewed from a later perspective as totally atypical, Cotterman displayed the most extraordinary energy in developing the Journal, contacting virtually every then living geneticist and soliciting contributions including one from Ullrich about the “Turner’s syndrome and Status Bonnevie-Ullrich,” which, Cotterman recalled, “was a 75-page manuscript which I translated in its entirety from the German” (Cotterman papers). In this paper Ullrich also pointed to the massive nuchal lymphedema seen in some (stillborn) fetuses with “massive edema of neck and arms” [Ullrich, 19491. Figure 10 of that paper illustrates beautifully what has since been recognized as a pathognomonic sign of the congenital lymphedema sequence, namely, the “lymphedema nails” deserving the designation “the Ullrich sign.” His contact with Professor Ullrich was mutually beneficial. It was Cotterman who acquainted Ullrich with the extensive Anglo-American literature on the “Turner syndrome,” then still largely unknown to German authors. Cotterman acquired a new enthusiasm which inspired a talk to the Genetics Society of America on the Status Bonnevie-Ullrich in a familial case later reported with Harold Falls as a companion paper to the Ullrich paper [Cotterman and Falls, 19491. Conversely, Cotterman wrote to Ruggles R. Gates to point out to him that in his discussion of the Turner syndrome in Vol. I1 of Human Genetics (1946) he had not quoted Ullrich. Cotterman was not tactful: “I presume that you had not run across Ullrich’s papers, and I think that it is somewhat unfortunate that neither you nor Griineberg make reference to this work, Ullrich‘s attempts to formulate the bleb theory in application to human teratology seem to me very thoughtful and cautious, if not entirely convincing. It was Ullrich‘s and Bonnevie’s papers which led
127
Engel to mutilate the whole idea (p. 489 of your Vol. I) with the consequence that Julius Bauer (Constitution and Disease) dismisses the idea as “strange” and substitutes his very convenient but rather uninformative concept of ‘Status degenerativus’ or ‘a mess in the chromosomes’ ” (Cotterman to Gates 9/27/49). Gates was not amused. “Dear Cotterman,” begins his reply (9/28/49 written while he was at Harvard). “Many thanks for your letter. I am sorry I overlooked Ullrich’s work on blebs although I was of course familiar with Bonnevie’s. I think pterygium colli is independent of blebs (a) because of its symmetry (b) because it is normal in the chimpanzee (Hum. Gen., p 800). I have always assumed that the webbing in the neck of the chimp. contained muscles but perhaps this is not the case.” Ullrich did not live to see Bauer’s “mess in the chromosomes” hypothesis verified, but he may have had an inkling in which way things were heading when he referred to the “pronounced gynecotropy” (ie., female predeliction) of the syndrome [Ullrich, 19591.Also, neither Gates nor Cotterman were in a position to apply the concepts of heterochrony or atavisms in aneupolidy to explain the occurrence of neck webbing in chimpanzees and in humans with 45,X chromosome constitution, i.e., the Ullrich-Turner syndrome [Opitz and Gilbert, 19901.
ACKNOWLEDGMENTS I am most grateful to Ms. Vicki Smith and Ms. LaVelle M. Spano for expert secretarial collaboration and to the Montana Department of Health and Environmental Sciences for support under Housebill 402. REFERENCES Cotterman CW, Falls HF (1949):Unilateral development anomalies in sisters (Status Bonnevie-Ullrich). Am J Hum Genet 1:203-213. Cotterman CW to R Ruggles Gates (9/27/49).Cotterman papers (Opitz, Helena, MT). Faber K (1923): “Nosography.” New York: P.B. Hoeber. Gates RR (1946):“Human Genetics.” New York: MacMillan vol 11, p 800. Gates RR to CW Cotterman, 9/28/49. Cotterman papers (Opitz, Helena, MT). Grunwald P, Kornfeld W (193516): Ein Fall von Elephantiasis lymphangiectatica bei einem vier Monate alten menschlichen Fetus. Beitr Pathol Anat allg Pathol 96:341-360. Opitz JM, Gilbert-Barness EF (1990):Reflections on the pathogenesis of Down syndrome. Am J Med Genet, Supplement 7:38-51. Siemens HW (1921):“Konstitutions- und Vererbungspathologie.” Berlin: Springer-Verlag. Starke KB (1950): Zur Diagnose des Status Bonnevie-Ullrich. Mschr Kinderhlk 98:420. Ullrich 0 (1930): Uber typische Kombinationsbilder multipler Abartungen. Z Kinderhlk 49271-276. Ullrich 0 (1937): Zur Phanogenese kombinierter Missbildungen. Mschr Kinderhlk 68:94-100. Ullrich 0 (1938): Neue Einblicke in die Entwicklungsmechanik multipler Abartungen und Fehlbildungen. Klin Wschr 17(6):185-190. Ullrich 0 (1949): Thrner’s syndrome and Status Bonnevie-UIlrich: A synthesis of animal phenogenetics and clinical observations on a typical complex of developmental anomalies. Am J Hum Genet 1:179-202. Ullrich 0 (1959): Embryo-fetale Hautschwellungen als phanogenetische Gestaltungsfaktoren. Mschr Kinderhlk 98:416-420. Wiedemann H-R (1985): Pfaundler-Deszendenz. Der Kinderarzt 16. 1599-1601.
Editorial Comment
Otto Ullrich: An Appreciation John M. Opitz Department of Medical Genetics, Shodair Children’s Hospital, Helena, Montana In several ways Meinhard von Pfaundler (18721947), one of the greatest German pediatricians (together with Adalbert Czerny) in the first half of this century, has had a remarkable influence on me. His third student to attain a Chairmanship was Rudolf Degkwitz (1889-1973), who was Professor of Pediatrics in Hamburg between 1932 and 1949 [Wiedemann, 19851. After my father’s death of tuberculosis Degkwitz became my pediatrician, diagnosed the same disease in me, and promptly had me bundled off to a sanatorium for 14 months with much rest, good food, fresh air, and regular doses of cod liver oil. Terror struck upon my return to Hamburg to live with my grandfather when it was decided that frequent transfusions of small amounts of fresh blood (directly from the donor) would strengthen my constitution and hasten my recovery. I lived in fear and dread of those weekly subway trips into the University Hospitals Hamburg-Eppendorf (later badly bombed) and was assuaged only by Degkwitz’s kindness in allowing me to play with his guinea pig named Mohrle (little carrot) who lived under the sofa in his waiting room. During those moments of respite, Degkwitz and my grandfather closeted themselves with a precious cigar and sip from a dwindling stock of sherry in his exam room in order (as I learned later) to vent their mutual ire about the present political regime and its catastrophic effect on all aspects of life. Both survived the serious reprisals visited on them by the regime but emigrated in a rage after the war never to return, Degkwitz to the U.S.A. and my grandfather to Cambridge in England. Through von Pfaundler’s fifth student to attain a chairmanship, Otto Ullrich (1894-19571, I have been privileged with the friendship of Ullrich’s student HansRudolf Wiedemann (Chairman in Kiel from 1961-1980) and Wiedemann’s student Jiirgen Spranger who has been Chairman in Mainz since 1974. One of von Pfaundler’s major merits as a scientist was his introduction of mathematical methods into the study of combined or complex manifestations in pediatrics. He invented and successfully applied the syntropy index, the most important intellectual advance in the study of diseases as specific entities since Sydenham and the advent of the germ theory [Faber, 19231. As early as Received for publication March 14,1990; revision received April 27, 1990. Address reprint requests to Dr. John M. Opitz, Shodair Children Hospital, 840 Helena Avenue, P.O. Box 5539, Helena, MT 59604.
0 1991 Wiley-Liss, Inc.
1911von Pfaundler pointed out that concurrent complex disease manifestations may have common cause. With respect to constitutional disorders he later coined the concept of multiple congenital anomalies (MCA) (multiple Abartungen), i.e., a core of malformations around which are grouped with variable frequency, numerous other signs of developmental abnormality. The constancy of the recurrence of the leading or core manifestations confirms the conditions as a discrete entity [Starke, 19501. The MCA concept was developed by Ullrich in three important ways. 1)He recognized that in certain typical MCA combinations (syndromes)family resemblance was abolished. This is now known as one of the most sensitive indicators of the presence of aneuploidy and was first discussed by Ullrich in connection with his delineation of what came to be called later the Ullrich-Turner syndrome. In his classic prototype description [19301he records that the child‘s “appearance still was somewhat odd [and that she] did not have any family resemblance a t all.” 2) He recognized and discussed in the same 1930 paper the similarity of many manifestations shared by the Ullrich-Turner and Down syndromes (e.g., shortness of stature, congenital lymphedema, webbing of the neck, ptosis, and “numerous individual malformations and anomalies of incomplete differentiation in the most diverse of organ systems”),concluding that these two conditions must share a similar pathogenesis “im Beginn der Ontogenese,” i.e., from the very beginning of development, which may be “. . . in der Keimanlage praedetermieniert” (predetermined in the germ cell) . .. durch idiotypische Momente . . . ,” i.e., by genetic causes [in the language of Siemens, 19211. 3) Long before his confrontation with Kristine Bonnevie’s work on the myelencephalic bleb mouse of Bagg and Little, Ullrich clearly outlined the picture of symmetrical congenital lymphedema, which resorbs gradually during the first year or two years of life and is associated with congenital redundancy of the skin at the nape of the neck and later pterygium colli, (facultative) movement disorders with webbing elsewhere, lymphedema of limbs, nail and nipple “dysplasia,” ptosis, other occasional cranial nerve palsies, and aortic coarctation. This is classical work as valid today as it was then. However, in his enthusiasm for the myelencephalic bleb theory he dismissed a bit too lightly the important observation of Griinwald and Kornfeld (1935/6) who reported on a 4-month-old human fetus with severe (cystic hygroma-like) lymphedema of neck,
Editorial Comment shoulders, back, anterior abdominal wall, and parts of arms and legs. They also observed a most conspicuous and extensive system of spongy cavernous spaces extruding from the jugular system into the upper mediastinum, a condition they likened to an arrest of the lymph system at an earlier developmental stage [Ullrich, 19381. It is a particularly appealing aspect of this man’s life that inspite of his genius he was not infallible. Yet most of what he accomplished remains a permanent contribution to our patrimony of developmental pediatrics and genetics. Ullrich’s main strength was in phenotype analysis, i.e., the analysis of the pathogenesis of MCA syndrome from a pediatric and a genetic perspective. In a masterful review on the subject from 1937he clearly stated that variability was due to the environmental and epigenetic factors, discussed the concept of pleiotropy, spoke of the myelencephalic bleb “consequences” in the developing mouse in terms which read like a modern description of a sequence, and emphasized the concept of heterogeneity, namely, that “phenotypically similar-appearing anomalies may arise due to genetically. . . totally different causes.”
EPILOGUE Shortly after the formation of the American Society of Human Genetics, H.J. Muller asked C.W. Cotterman to become editor of the American Journal of Human Genetics. Viewed from a later perspective as totally atypical, Cotterman displayed the most extraordinary energy in developing the Journal, contacting virtually every then living geneticist and soliciting contributions including one from Ullrich about the “Turner’s syndrome and Status Bonnevie-Ullrich,” which, Cotterman recalled, “was a 75-page manuscript which I translated in its entirety from the German” (Cotterman papers). In this paper Ullrich also pointed to the massive nuchal lymphedema seen in some (stillborn) fetuses with “massive edema of neck and arms” [Ullrich, 19491. Figure 10 of that paper illustrates beautifully what has since been recognized as a pathognomonic sign of the congenital lymphedema sequence, namely, the “lymphedema nails” deserving the designation “the Ullrich sign.” His contact with Professor Ullrich was mutually beneficial. It was Cotterman who acquainted Ullrich with the extensive Anglo-American literature on the “Turner syndrome,” then still largely unknown to German authors. Cotterman acquired a new enthusiasm which inspired a talk to the Genetics Society of America on the Status Bonnevie-Ullrich in a familial case later reported with Harold Falls as a companion paper to the Ullrich paper [Cotterman and Falls, 19491. Conversely, Cotterman wrote to Ruggles R. Gates to point out to him that in his discussion of the Turner syndrome in Vol. I1 of Human Genetics (1946) he had not quoted Ullrich. Cotterman was not tactful: “I presume that you had not run across Ullrich’s papers, and I think that it is somewhat unfortunate that neither you nor Griineberg make reference to this work, Ullrich‘s attempts to formulate the bleb theory in application to human teratology seem to me very thoughtful and cautious, if not entirely convincing. It was Ullrich‘s and Bonnevie’s papers which led
127
Engel to mutilate the whole idea (p. 489 of your Vol. I) with the consequence that Julius Bauer (Constitution and Disease) dismisses the idea as “strange” and substitutes his very convenient but rather uninformative concept of ‘Status degenerativus’ or ‘a mess in the chromosomes’ ” (Cotterman to Gates 9/27/49). Gates was not amused. “Dear Cotterman,” begins his reply (9/28/49 written while he was at Harvard). “Many thanks for your letter. I am sorry I overlooked Ullrich’s work on blebs although I was of course familiar with Bonnevie’s. I think pterygium colli is independent of blebs (a) because of its symmetry (b) because it is normal in the chimpanzee (Hum. Gen., p 800). I have always assumed that the webbing in the neck of the chimp. contained muscles but perhaps this is not the case.” Ullrich did not live to see Bauer’s “mess in the chromosomes” hypothesis verified, but he may have had an inkling in which way things were heading when he referred to the “pronounced gynecotropy” (ie., female predeliction) of the syndrome [Ullrich, 19591.Also, neither Gates nor Cotterman were in a position to apply the concepts of heterochrony or atavisms in aneupolidy to explain the occurrence of neck webbing in chimpanzees and in humans with 45,X chromosome constitution, i.e., the Ullrich-Turner syndrome [Opitz and Gilbert, 19901.
ACKNOWLEDGMENTS I am most grateful to Ms. Vicki Smith and Ms. LaVelle M. Spano for expert secretarial collaboration and to the Montana Department of Health and Environmental Sciences for support under Housebill 402. REFERENCES Cotterman CW, Falls HF (1949):Unilateral development anomalies in sisters (Status Bonnevie-Ullrich). Am J Hum Genet 1:203-213. Cotterman CW to R Ruggles Gates (9/27/49).Cotterman papers (Opitz, Helena, MT). Faber K (1923): “Nosography.” New York: P.B. Hoeber. Gates RR (1946):“Human Genetics.” New York: MacMillan vol 11, p 800. Gates RR to CW Cotterman, 9/28/49. Cotterman papers (Opitz, Helena, MT). Grunwald P, Kornfeld W (193516): Ein Fall von Elephantiasis lymphangiectatica bei einem vier Monate alten menschlichen Fetus. Beitr Pathol Anat allg Pathol 96:341-360. Opitz JM, Gilbert-Barness EF (1990):Reflections on the pathogenesis of Down syndrome. Am J Med Genet, Supplement 7:38-51. Siemens HW (1921):“Konstitutions- und Vererbungspathologie.” Berlin: Springer-Verlag. Starke KB (1950): Zur Diagnose des Status Bonnevie-Ullrich. Mschr Kinderhlk 98:420. Ullrich 0 (1930): Uber typische Kombinationsbilder multipler Abartungen. Z Kinderhlk 49271-276. Ullrich 0 (1937): Zur Phanogenese kombinierter Missbildungen. Mschr Kinderhlk 68:94-100. Ullrich 0 (1938): Neue Einblicke in die Entwicklungsmechanik multipler Abartungen und Fehlbildungen. Klin Wschr 17(6):185-190. Ullrich 0 (1949): Thrner’s syndrome and Status Bonnevie-UIlrich: A synthesis of animal phenogenetics and clinical observations on a typical complex of developmental anomalies. Am J Hum Genet 1:179-202. Ullrich 0 (1959): Embryo-fetale Hautschwellungen als phanogenetische Gestaltungsfaktoren. Mschr Kinderhlk 98:416-420. Wiedemann H-R (1985): Pfaundler-Deszendenz. Der Kinderarzt 16. 1599-1601.
