- Email: [email protected]
Russell dwarf versus Silversyndrome
10 6 6
Letters to the Editor
for that matter other heat-labile serum factors, are the "protective factor." 4. For the reason given in the preceding paragraph, we felt no compelling need to repeat the Fothergill-Wright protocol which could have misled us greatly if the endogenous complement therein was inactive. We did attempt to get some agammaglobulinemic sera to use as a source of human complement from Dr. Gitlin, which Norden and associates had used for their study. None was available to us and we could not obtain any locally. 5. In summation, I think that it is abundantly clear that guinea pig complement worked in our system with the organism we used. I feel also that this whole disagreement may be referable to a difference in strains. We used one strain of H. influenzae B and one well may ask, which Mpairwe doesn't, if several strains of H. influenzae B are similarly unsusceptible. Currently, we have a grant proposal pending with the N I H to study such strain differences. In two letters to Dr. Mpairwe, I have asked him to send me Uganda strains which are the source of the infection he discusses in the second to the last paragraph of his letter, but he has consistently ignored this request. Alternatively, if Mpairwe is genuinely interested in disproving our thesis, he should (it seems t o me) provide himself with some laboratory data from Iocal cases which seem abundant in Uganda. (It is entirely possible, because of social and economic conditions in that country as well as probably judicious use of antibiotics there, that maternal antibody of good H. influenzae titer is passed on to infants.) For now, the increasing incidence of neonatal It. influenzae meningitis in this country argues that the newborn infant is at a greater risk (as we stated) than his counterpart of 40 years ago.
Charles D. Graber, Ph.D. Medical University of South Carolina 80 Barre St. Charleston, S. C. 29401
The Journal o/ Ped~trics June 1972
Comment To the Editor: The correspondence between Dr. Mpairwe of Uganda and Dr. Graber of South Carolina was extremely interesting to me. The whole question of methodology in H. influenzae studies, which are now becoming popular, is an important one. I must admit that I believe Dr. Mpairwe's case is appropriate. We found that in many of the samples of human serum, heat inactivation (56 ~ C. per 30 minutes) destroyed inhibitory activity which was not restored by addition of guinea pig complement. In our laboratory, all serum samples are tested unheated. We use human complement, too. Fothergill and Wright, as you will recall, used defibrinated whole blood which is far more complex. I would agree with Dr. Graber that there are strain differences, too. We have tested serum from patients against stock strains and also against their own H. influenzae with different results. There is much yet to learn about immunity to Pfeiffer's bacillus. Incidentally, in the past 15 years, at Vanderbilt there has been only one H. influenzae meningitis patient who was two weeks of age--none younger.
Sarah H. Sell, M.D. Department o[ Pediatrics Vanderbilt University School o[ Medicine Nashville, Tenn. 37203 Editor's note: The letter from Dr. Mpairwe and the reply from Dr. Graber were submitted to Dr. Sarah Sell for her evaluation. We are indebted to her for the above comment. It appears that the "secrets" of H. influenzae type B have not all been disclosed.
Russell dwarf versus Silver syndrome To the Editor:
REFERENCE I. Schneerson, R., Rodrigues, L. P., Parke, J. C., Jr., and Robbins, J. B.: Immunity to disease caused by Hemophilus influenzae type b. II. Specificity and some biologic characteristics of "natural," infection-acquired, and immunization-induced antibodies to the capsular polysaecharlde of Hemophilus influenzae type b, J. Immunol. 107: 1081, 1971.
Gareis and associates 1 quote me, among others, as suggesting that the patients described by Russell and Silver were similar and that the clinical entity be designated the "Russell-Silver" syndrome. Nothing could be further from the truth. In private correspondence and conversations over the p a s t few years, I have suggested to Drs. Rimoin, Warkany, and Gorlin that the two entities should be separated. In 1963,2 I described
Volume 80 Number 6
Letters to the Editor
Table I
Form o[ intrauterine dwarfism Seckel Silver Russell
Cranio[acial relationship face > cranium face ~ cranium face < cranium
three patients with the "Russell" form of intrauterine dwarfism and in 1964,a one patient with the "Seckel" form. In both reports, I differentiated my patients from those described by Silver and I indicated my unease with the imprecise definition of the "Silver" syndrome. Your readers may find helpful my hypothesis, adapted from Seckel, that the study of craniofacial proportions may be used, at times, to differentiate three types of intrauterine dwarfs (Table
I). Another helpful observation is that head circumference correlates better with body length than with body weight or with age. (See references20 to 22 in my 1964 article. 8) Applying these two parameters (craniofacial proportion and the better correlation of head circumference to body length) to the "Russell" dwarf, one finds an intrauterine dwarf whose head circumference is normal for his body length, but whose small face and wide-open fontanelle lead one to suspect hydrocephalus. I feel this is an important clinical distinction as many of these patients have been unnecessarily subjected to pneumoencephalography. The same parameters applied to the "Seckel" dwarf reveals an intrauterine dwarf whose head is quite microcephalic (bird-headed) and whose face appears relatively large.S, 4 However, the craniofacial relationship in these patients is affected by age. Thus one "Russell" dwarf "grew into" his head size, i.e., the craniofacial proportions became more normal with age, 2 and the "Seckel" dwarf did not appear microcephalic or grotesque at the age of seven months, a I agree with Gareis and associates 1 that asymmetry is not a prerequisite for the clinical diagnosis of the "Russell" syndrome; however, I feel it is sine qua non for the diagnosis of the "Silver" syndrome,s My major dissatisfaction with the "Silver" syndrome is its diagnosis in patients who are not even intrauterine dwarfs. 5 Concerning the mechanism of hypoglycemia in these patients, one of our Russell dwarfs probably died of congenital adrenal hypoplasia but blood sugars were not followed3 The familial occurrence of
1 06 7
the Russell dwarf was probably first reported by G r a y 6 in 1959 and recently by CallaghanY I would place the two maIe siblings reported by Callaghan into the "Russell" group because their heads are reported to be "disproportionately" large, whereas the author places them in the "Silver" group because of their asymmetry. Contrary to the statement by Fuleihan and associates, s the hyphenated eponym "Russell-Silver" was first published by Black9 in 1961. I worry about statements in the literature suggesting that most of these children are of normal intelligence1, s Only the patients of Rimoin~~ and one of my own 2 have been followed through their teens. Rimoin's male twins were "sophomores in college" and "active in sports"; my patient's retardation (Case 2) was not suspected until he was at least 10 years old. In summary, the impropriety of combining the Russell and the Silver types of intrauterine dwarfism into a single syndrome is discussed, and a method of distinguishing three recognized syndromes (Russell, Seckel, and Silver) is presented.
Glenn C. Szalay, M.D. Department of Pediatrics Southern Cali[ornia Permanente Medical Group Harbor City, Call[. 90710 REFERENCES 1. Gareis, F. J., Smith, D. W., and Summitt, R. L.: The Russell-Silver syndrome without asymmetry, J. PEDIATR. 79: 775, 1971. 2. Szalay, G. C.: Pseudohydrocephalus in dwarfs: The Russell dwarf, J. PEDIATR. 63: 622, 1963. 3. Szalay, G. C.: Intrauterine growth retardation versus Silver's syndrome, J. PEDIATR. 64: 234, 1964. 4. McKuslck, V. A., Mahloudji, M., Abbott, 1V~. H., et al.: Seckel's bird-headed dwarfism, N. Engl. J. Med. 277: 279, 1967. 5. Silver, H. K., and Grusky, F. L.: Syndrome of congenital hemihypertrophy and elevated urinary gonadotropins, Am. J. Dis. Child. 93: 559, 1957. 6. Gray, O. P.: Dwarfism ?Cockayne ?Russell type, Proc. R. Soc. Med. 52: 304, 1959. 7. Callaghan, K. A.: Asymmetrical dwarfism, or Silver's syndrome, in two male siblings, Med. J. Aust. 2: 789, 1970. 8. Fuleihan, D. S., Der Kaloustian, V. M., and Najjar, S. S.: The Russell-Silver syndrome: Report of three siblings, J. PEDIATR. 78: 654, 1971. 9. Black, J.: Low birth weight dwarfism~ Arch. Dis, Child, 36: 633, I961o
10 6 8
Letters to the Editor
10. Rimoin, D. L.: The Silver syndrome in twins, Birth Defects: Original Article Series 5(2): 183, 1969.
Reply To the Editor: We sincerely apologize for indicating that Szalay favored the designation Russell-Silver syndrome.1 The following are a few comments relative to Dr. Szalay's letter: 1. The purpose of our report was to better delineate a particular pattern of malformation and to emphasize that skeletal asymmetry is a variable feature of this growth disorder. This pattern of altered morphogenesis was independently recognized by Russelt2 and by Silver and associates, a hence the designation Russell-Silver syndrome. In the early diagnosis and descriptions of a malformation syndrome it is often very difficult to appreciate the clinical limits of the apparent disorder. With time and the recognition of more cases a better perspective can usually be achieved. Silver's2 initial report placed emphasis on "hemihypertrophy and elevated urinary gonadotropins." Our own present perspective on the disorder is that asymmetry (preferring that term to hemihypertrophy) is a variable feature and that evidence of early aberrant gonadotropin production and/or early adolescent changes are an unusual finding in the Russell-Silver syndrome. We agree with Szalay that some of the patients reported by Silver~ do not have what we would call the Russell-Silver syndrome. However, the majority of them do; hence we feel that the term RussellSilver syndrome is valid and tends to distinguish this clinical entity. A word about the variability of skeletal asymmetry or malproportion in Russell-Silver "syndrome. In the report of Szalay~ on the "Rnssell dwarf" one patient had documented asymmetry, one had relatively short symmetrical humeri, and the other had no documented asymmetry or malproportionment. Thus the variability is noted in his cases, as in the original cases described by Russell.2 The high proportion of "Silver syndrome" cases who have asymmetry is, we feel, due to a diagnostic ascertainment bias in terms of asymmetry for cases which we would interpret as Russell-Silver syndrome plus additional n o n Russell-Silver syndrome cases which were included because of an early tendency to diagnostically link the nonspecific feature of skeletal asymmetry and Silver's syndrome. This type of single feature ascertainment bias has led to initial
The Journal of Pediatrics June 1972
diagnostic confusion in other syndromes, for example, the early, undue diagnostic association of the nonspecific feature of web neck and Turner's syndrome. We can now state that web neck is an inconsistent feature of XO Turner's syndrome; it may be found in at least six other syndromes and as an isolated anomaly. The following generality merits re-emphasis: The clinical diagnosis of a malformation syndrome is dependent on evaluation of the total pattern of abnormal development, and individual defects are, with rare exception, not pathognomonic for a particular syndrome. 2. We would disagree with the differential value of variant craniofaciaI relationships between the Russell and Silver syndromes. The major reason is that we have come to recognize only one clinical disorder among the patients reported as Russell's or Silver's syndrome and this we designate as the Russell-Silver syndrome. Beyond this we have not recognized another specific clinical entity among the reported cases. If Dr. Szalay or others have recognized another specific clinical entity besides the Russell-Silver syndrome among those reported as Russell's syndrome or Silver's syndrome, we would be anxious to hear from them. The general tendency among the Russell-Silver syndrome patients is for the cranium to appear relatively large in relationship to the facies whereas the head circumference measurement is usually in the lower range of normal for age.
David W. Smith, M.D. Frank ]. Gareis, M.D. Department o[ Pediatrics University o[ Washington Seattle, Wash. 98105 Robert L. Summitt, M.D. Department o[ Pediatrics 860 Madison Memphis, Tenn. 38103 REFERENCES 1. Gareis, F. J., Smith, D. W., and Summitt, R. L.: The Russell-Silver syndrome with asymmetry, J. PEDIATR.79: 775, 1971. 2. Russell, A.: A syndrome of "intra-uterine" dwarfism recognizable at birth with craniofacial dysostosis, disproportionately short arms, and other anomalies (5 examples), Proc. R. Soc. Med. 47: 1040, 1954. 3. Silver, H. K., Kiyasu, W., George, J., and .Deamer, W. C.: Syndrome of congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropins, Pediatrics 12: 368, 1953.
Letters to the Editor
for that matter other heat-labile serum factors, are the "protective factor." 4. For the reason given in the preceding paragraph, we felt no compelling need to repeat the Fothergill-Wright protocol which could have misled us greatly if the endogenous complement therein was inactive. We did attempt to get some agammaglobulinemic sera to use as a source of human complement from Dr. Gitlin, which Norden and associates had used for their study. None was available to us and we could not obtain any locally. 5. In summation, I think that it is abundantly clear that guinea pig complement worked in our system with the organism we used. I feel also that this whole disagreement may be referable to a difference in strains. We used one strain of H. influenzae B and one well may ask, which Mpairwe doesn't, if several strains of H. influenzae B are similarly unsusceptible. Currently, we have a grant proposal pending with the N I H to study such strain differences. In two letters to Dr. Mpairwe, I have asked him to send me Uganda strains which are the source of the infection he discusses in the second to the last paragraph of his letter, but he has consistently ignored this request. Alternatively, if Mpairwe is genuinely interested in disproving our thesis, he should (it seems t o me) provide himself with some laboratory data from Iocal cases which seem abundant in Uganda. (It is entirely possible, because of social and economic conditions in that country as well as probably judicious use of antibiotics there, that maternal antibody of good H. influenzae titer is passed on to infants.) For now, the increasing incidence of neonatal It. influenzae meningitis in this country argues that the newborn infant is at a greater risk (as we stated) than his counterpart of 40 years ago.
Charles D. Graber, Ph.D. Medical University of South Carolina 80 Barre St. Charleston, S. C. 29401
The Journal o/ Ped~trics June 1972
Comment To the Editor: The correspondence between Dr. Mpairwe of Uganda and Dr. Graber of South Carolina was extremely interesting to me. The whole question of methodology in H. influenzae studies, which are now becoming popular, is an important one. I must admit that I believe Dr. Mpairwe's case is appropriate. We found that in many of the samples of human serum, heat inactivation (56 ~ C. per 30 minutes) destroyed inhibitory activity which was not restored by addition of guinea pig complement. In our laboratory, all serum samples are tested unheated. We use human complement, too. Fothergill and Wright, as you will recall, used defibrinated whole blood which is far more complex. I would agree with Dr. Graber that there are strain differences, too. We have tested serum from patients against stock strains and also against their own H. influenzae with different results. There is much yet to learn about immunity to Pfeiffer's bacillus. Incidentally, in the past 15 years, at Vanderbilt there has been only one H. influenzae meningitis patient who was two weeks of age--none younger.
Sarah H. Sell, M.D. Department o[ Pediatrics Vanderbilt University School o[ Medicine Nashville, Tenn. 37203 Editor's note: The letter from Dr. Mpairwe and the reply from Dr. Graber were submitted to Dr. Sarah Sell for her evaluation. We are indebted to her for the above comment. It appears that the "secrets" of H. influenzae type B have not all been disclosed.
Russell dwarf versus Silver syndrome To the Editor:
REFERENCE I. Schneerson, R., Rodrigues, L. P., Parke, J. C., Jr., and Robbins, J. B.: Immunity to disease caused by Hemophilus influenzae type b. II. Specificity and some biologic characteristics of "natural," infection-acquired, and immunization-induced antibodies to the capsular polysaecharlde of Hemophilus influenzae type b, J. Immunol. 107: 1081, 1971.
Gareis and associates 1 quote me, among others, as suggesting that the patients described by Russell and Silver were similar and that the clinical entity be designated the "Russell-Silver" syndrome. Nothing could be further from the truth. In private correspondence and conversations over the p a s t few years, I have suggested to Drs. Rimoin, Warkany, and Gorlin that the two entities should be separated. In 1963,2 I described
Volume 80 Number 6
Letters to the Editor
Table I
Form o[ intrauterine dwarfism Seckel Silver Russell
Cranio[acial relationship face > cranium face ~ cranium face < cranium
three patients with the "Russell" form of intrauterine dwarfism and in 1964,a one patient with the "Seckel" form. In both reports, I differentiated my patients from those described by Silver and I indicated my unease with the imprecise definition of the "Silver" syndrome. Your readers may find helpful my hypothesis, adapted from Seckel, that the study of craniofacial proportions may be used, at times, to differentiate three types of intrauterine dwarfs (Table
I). Another helpful observation is that head circumference correlates better with body length than with body weight or with age. (See references20 to 22 in my 1964 article. 8) Applying these two parameters (craniofacial proportion and the better correlation of head circumference to body length) to the "Russell" dwarf, one finds an intrauterine dwarf whose head circumference is normal for his body length, but whose small face and wide-open fontanelle lead one to suspect hydrocephalus. I feel this is an important clinical distinction as many of these patients have been unnecessarily subjected to pneumoencephalography. The same parameters applied to the "Seckel" dwarf reveals an intrauterine dwarf whose head is quite microcephalic (bird-headed) and whose face appears relatively large.S, 4 However, the craniofacial relationship in these patients is affected by age. Thus one "Russell" dwarf "grew into" his head size, i.e., the craniofacial proportions became more normal with age, 2 and the "Seckel" dwarf did not appear microcephalic or grotesque at the age of seven months, a I agree with Gareis and associates 1 that asymmetry is not a prerequisite for the clinical diagnosis of the "Russell" syndrome; however, I feel it is sine qua non for the diagnosis of the "Silver" syndrome,s My major dissatisfaction with the "Silver" syndrome is its diagnosis in patients who are not even intrauterine dwarfs. 5 Concerning the mechanism of hypoglycemia in these patients, one of our Russell dwarfs probably died of congenital adrenal hypoplasia but blood sugars were not followed3 The familial occurrence of
1 06 7
the Russell dwarf was probably first reported by G r a y 6 in 1959 and recently by CallaghanY I would place the two maIe siblings reported by Callaghan into the "Russell" group because their heads are reported to be "disproportionately" large, whereas the author places them in the "Silver" group because of their asymmetry. Contrary to the statement by Fuleihan and associates, s the hyphenated eponym "Russell-Silver" was first published by Black9 in 1961. I worry about statements in the literature suggesting that most of these children are of normal intelligence1, s Only the patients of Rimoin~~ and one of my own 2 have been followed through their teens. Rimoin's male twins were "sophomores in college" and "active in sports"; my patient's retardation (Case 2) was not suspected until he was at least 10 years old. In summary, the impropriety of combining the Russell and the Silver types of intrauterine dwarfism into a single syndrome is discussed, and a method of distinguishing three recognized syndromes (Russell, Seckel, and Silver) is presented.
Glenn C. Szalay, M.D. Department of Pediatrics Southern Cali[ornia Permanente Medical Group Harbor City, Call[. 90710 REFERENCES 1. Gareis, F. J., Smith, D. W., and Summitt, R. L.: The Russell-Silver syndrome without asymmetry, J. PEDIATR. 79: 775, 1971. 2. Szalay, G. C.: Pseudohydrocephalus in dwarfs: The Russell dwarf, J. PEDIATR. 63: 622, 1963. 3. Szalay, G. C.: Intrauterine growth retardation versus Silver's syndrome, J. PEDIATR. 64: 234, 1964. 4. McKuslck, V. A., Mahloudji, M., Abbott, 1V~. H., et al.: Seckel's bird-headed dwarfism, N. Engl. J. Med. 277: 279, 1967. 5. Silver, H. K., and Grusky, F. L.: Syndrome of congenital hemihypertrophy and elevated urinary gonadotropins, Am. J. Dis. Child. 93: 559, 1957. 6. Gray, O. P.: Dwarfism ?Cockayne ?Russell type, Proc. R. Soc. Med. 52: 304, 1959. 7. Callaghan, K. A.: Asymmetrical dwarfism, or Silver's syndrome, in two male siblings, Med. J. Aust. 2: 789, 1970. 8. Fuleihan, D. S., Der Kaloustian, V. M., and Najjar, S. S.: The Russell-Silver syndrome: Report of three siblings, J. PEDIATR. 78: 654, 1971. 9. Black, J.: Low birth weight dwarfism~ Arch. Dis, Child, 36: 633, I961o
10 6 8
Letters to the Editor
10. Rimoin, D. L.: The Silver syndrome in twins, Birth Defects: Original Article Series 5(2): 183, 1969.
Reply To the Editor: We sincerely apologize for indicating that Szalay favored the designation Russell-Silver syndrome.1 The following are a few comments relative to Dr. Szalay's letter: 1. The purpose of our report was to better delineate a particular pattern of malformation and to emphasize that skeletal asymmetry is a variable feature of this growth disorder. This pattern of altered morphogenesis was independently recognized by Russelt2 and by Silver and associates, a hence the designation Russell-Silver syndrome. In the early diagnosis and descriptions of a malformation syndrome it is often very difficult to appreciate the clinical limits of the apparent disorder. With time and the recognition of more cases a better perspective can usually be achieved. Silver's2 initial report placed emphasis on "hemihypertrophy and elevated urinary gonadotropins." Our own present perspective on the disorder is that asymmetry (preferring that term to hemihypertrophy) is a variable feature and that evidence of early aberrant gonadotropin production and/or early adolescent changes are an unusual finding in the Russell-Silver syndrome. We agree with Szalay that some of the patients reported by Silver~ do not have what we would call the Russell-Silver syndrome. However, the majority of them do; hence we feel that the term RussellSilver syndrome is valid and tends to distinguish this clinical entity. A word about the variability of skeletal asymmetry or malproportion in Russell-Silver "syndrome. In the report of Szalay~ on the "Rnssell dwarf" one patient had documented asymmetry, one had relatively short symmetrical humeri, and the other had no documented asymmetry or malproportionment. Thus the variability is noted in his cases, as in the original cases described by Russell.2 The high proportion of "Silver syndrome" cases who have asymmetry is, we feel, due to a diagnostic ascertainment bias in terms of asymmetry for cases which we would interpret as Russell-Silver syndrome plus additional n o n Russell-Silver syndrome cases which were included because of an early tendency to diagnostically link the nonspecific feature of skeletal asymmetry and Silver's syndrome. This type of single feature ascertainment bias has led to initial
The Journal of Pediatrics June 1972
diagnostic confusion in other syndromes, for example, the early, undue diagnostic association of the nonspecific feature of web neck and Turner's syndrome. We can now state that web neck is an inconsistent feature of XO Turner's syndrome; it may be found in at least six other syndromes and as an isolated anomaly. The following generality merits re-emphasis: The clinical diagnosis of a malformation syndrome is dependent on evaluation of the total pattern of abnormal development, and individual defects are, with rare exception, not pathognomonic for a particular syndrome. 2. We would disagree with the differential value of variant craniofaciaI relationships between the Russell and Silver syndromes. The major reason is that we have come to recognize only one clinical disorder among the patients reported as Russell's or Silver's syndrome and this we designate as the Russell-Silver syndrome. Beyond this we have not recognized another specific clinical entity among the reported cases. If Dr. Szalay or others have recognized another specific clinical entity besides the Russell-Silver syndrome among those reported as Russell's syndrome or Silver's syndrome, we would be anxious to hear from them. The general tendency among the Russell-Silver syndrome patients is for the cranium to appear relatively large in relationship to the facies whereas the head circumference measurement is usually in the lower range of normal for age.
David W. Smith, M.D. Frank ]. Gareis, M.D. Department o[ Pediatrics University o[ Washington Seattle, Wash. 98105 Robert L. Summitt, M.D. Department o[ Pediatrics 860 Madison Memphis, Tenn. 38103 REFERENCES 1. Gareis, F. J., Smith, D. W., and Summitt, R. L.: The Russell-Silver syndrome with asymmetry, J. PEDIATR.79: 775, 1971. 2. Russell, A.: A syndrome of "intra-uterine" dwarfism recognizable at birth with craniofacial dysostosis, disproportionately short arms, and other anomalies (5 examples), Proc. R. Soc. Med. 47: 1040, 1954. 3. Silver, H. K., Kiyasu, W., George, J., and .Deamer, W. C.: Syndrome of congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropins, Pediatrics 12: 368, 1953.