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PKU-hypothesis concerning failures of screening
Volume 96 Number 5
recessively inherited vaginal atresia and its variable association with rectovaginal fistulas and postaxial polydactyly. Much later, Kaufman, 2 on the basis of a single additional case, suggested that cortgenital heart disease was another, occasional manifestation of the syndrome. In 1977, McKusick ~ proposed the term Kaufman syndrome. We felt that the importance of McKusick's contributions far outweighed that of Kaufman, and offered this new term before Kaufman syndrome had time to come into current use. In general, however, we support Dr. Heeht's plea. Let us hope that some international body will devise a more uniform terminology, as did the international group which adopted and later revised the nomenclature for skeletal dysplasias.4 Certainly, there are areas where uniformity would be helpful. For instance, we ought to agree whether it should be Wiedemann-Beckwith or Beckwith-Wiedemann. We should dispose with first names in eponyms (Robi n syndrome instead of Pierre Robin syndrome) and perhaps drop third names from triple eponyms, such as Charcot-Marie-Tooth. In some other areas, however, we may not yet be ready for uniformity. Which is more appropriate': Tetraphocomelia with cleft palate,. S-C syndrome, Roberts syndrome, or pseudothalidomide syndrome? Are we dealing with one or two syndromes? Opinions are still divided. An early decision in favor of one of these tel-ms may prove troublesome later. We believe that there is a legitimate place for the apparent chaos. In the early stages of syndrome delineation adherence to any standard system of nomenclature is often neither feasible nor desirable. Initial labels are often intentionally vague, to be :superseded by more definitive terms as more knowledge is gained. Gertrud Hurler called her syndrome "A type of multiple anomalies, mainly of the skeletal system. ''~ As more cases were recognized, Hurler disease seemed a suitable name. Attempts to get rid of the eponym resulted in gargoylism (descriptive but demeaning and therefore unacceptable today) and lipochondrodystrophy (misleading, since the stored material proved not to be a lipid). Correlation of biochemical, clinical and genetic studies led to McKusick's numerical classification, in which the disorder became mucopolysaccharidosis I, The discovery of the enzyme defect permitted coinage of the more specific (though not necessarily preferable) term a-L-iduronase deficiency, Hurler form.4 Syndrome terms will evolve, often for the better, sometimes for the worse and, as language in general, not always to the liking of the purists. Let us hope for some modest progress toward uniformity but realize that there is a legitimate place for diversity, and even for apparent chaos. Meinhard Robinow, M.D. Wright State University School of Medicine Department of Pediatrics Dayton, OH 45404 Anthony Shaw,, M.D. University of Virginia School of Medicine Department of Surgery Charlottesville, VA 22908 REFERENCES 1. Hecht FA: A common toothbrush for dysmorphology, J PED~A'r~.95:812, 1979.
Editorial correspondence
9 53
2.
Kaufman RL, Hartman AF, McAlister WH: Family studies in congenital heart disease. II. A syndrome of hydrometrocolpos, postaxial polydactyly and congenital heart disease, Birth Defects 8:85, 1972. 3. McKusick VA: The William Allen Memorial Lecture. Genetic nosology. Three approaches, Am J Hum Genet 3:105, 1978. 4. International Nomenclature of Constitutional Diseases of Bone, Revision--May 1977, Am J Med Genet 3:21, 1979. 5. Hurler G: Ober einen Typ multipler Abartungen, vorwiegend am Skelettsystem, Ztschr Kinderh 24:220, 1920.
PKU--hypothesis concerning failures of screening To the Editor. Several screening programs for phenylketonuria (PKU) in the United States have reported a 5 to 10% incidence of missed cases, most of which arepresumed to be due to the lack of a centralized laboratory? Hohzman et aF has postulated that some cases of PKU are missed because their blood phenylalanine concentration rises more slowly than usual after birth. I would like to propose a biochemical hypothesis to account for a portion of these missed cases. My premise is that a fetal phenylalanine hydroxylase enzyme can persist into neonatal life. Thus, a newborn infant with "classical" phenylketonuria and persistence of a fetal isozyme could have a screening test performed and be reported as normal because the enzyme keeps the blood phenylalanine at normal levels. When the fetal isozyme no longer functions, and if the infant has no "adult" phenylalanine hydroxylase, the blood phenylalanine would eventually rise. Unfortunately,9 by that time the child would have been discharged home with a normal test. Several investigators have shown the existence of phenylalanine hydroxylase isozymes ~ and modifiersr and Barranger et aP have reported the existence of a fetal isozyme, whidl would lend support to my hypothesis. It is also interesting to note that PKU cases are rarely missed in England, where screening occurs at a later date than in this country. Julian L. Berman, M.D. The Chicago Medical School 2020 West Ogden Ave. Chicago, IL 60612 REFERENCES 1. Sepe SJ, Levy HL, and Mount FW: An evaluation of routine follow-up blood screening of infants for phenylketonuria, N Engl J Med 300:606, 1979. 2. Holtzman NA, Mellits ED, and Kallman CN: Neonatal screening for phenylketonuria. II. Age dependence of initial phenylalanine in infants with PKU, Pediatrics 53:353, 1974. 3. Parker CE, Barranger J, Newhouse R, and Bessman S: Studies of the isozymes of phenylalanine hydroxylase in humans, Biochem Med 1"7:8, 1977.
9 54
Editorial correspondence
4.
Donlon J, and Kaufman S: Modification of the multiple forms of rat hepatic phenylalanine hydroxylase by in vitro phosphorylation, Biochem Biophys Res Commun 78:1011, 1977. 5. Barranger JA, Gelger PJ, Huzino A, and Bessman SP: Isozymes of phenylalanine hydroxylase. Science 175:903, 1972.
Simultaneous recovery of ampicillinsensitive and ampicillin-resistant H. influenzae from blood To the Editor: The simultaneous isolation of both ampicillin-sensitive and ampicillin-resistant Haemophilus influenzae from patients deserves special consideration by clinicians lreating infections if the disease progresses despite what appears to be adequate and appropriate therapy. Jubelirer and Yeager's repoW of two patients from whom ampicillin-sensitive H. influenzae were isolated from cerebrospinal fluid and ampicillin-resistant isolates were recovered from blood underscores the clinical significance of this observation. We recently have seen an adult patient from whose blood ampicillin-susceptible and ampicillin-resistant H. influenzae were isolated simultaneously. Pediatricians encounter bacteremia caused by H. influenzae more frequently than do physicians treating adults, and !t is particularly important that the heterogeneity of bacterial populations in regard to antibiotic susceptibility be appreciated in this context. The two strains of H. influenzae encountered in our patient were morphologically indistinguishable and were recognized only when rapid beta lactamase determinations and disc diffusion susceptibility tests~ differed. It behooves both the clinical microbiologist and the clinician to remember that a bacterial colony may not be representative of the potential genetic heterogeneity of the bacterial population as a whole. Recognition of bacterial subpopulations is dependent on variation in phenotypically recognizable characteristics. Detection of antibiotic-resistant subpopulations among morphologically indistinguishable colony types may be contingent on the chance testing of colonies which express susceptibility differences. In the face of treatment failure with seemingly appropriate drugs, reculture of infected sites is useful to detect population shifts in the predominant phenotype. If the specimen is unrepeatable or involves inadvisable invasive techniques, examination of additional representative colonies of the bacterial isolate for initially undetected antibiotic resistant subpopulations may be of value. David G. Beckwith, Ph.D. Clinical Microbiologist "Department of Pathology St. Luke's Hospital Bethlehem, PA 18015
The Journal of Pediatrics May 1980 REFERENCES
1. Jubelier DP, and Yeager AS: Simultaneous recovery of ampicillin-sensitive and ampicillin-resistant organisms in Haemophilus influenzae type b meningitis, J PEDIATR 95:415, i979. 2. NCCLS performance standards for antimicrobic disc susceptibility tests, ed 2, Vilianova, Pa., 1979, NCCLS, p 11.
Colon cancer after Wilms tumor To the Editor: Sabio et al 1 recently described a patient who developed adenocarcinoma of the colon after treatments for Wilms tumor. I Msh to report a second patient with the same sequence of multiple primary cancers. CASE REPORT
An abdominal mass was found in an 11-month-old boy in 1948. Intravenous pyelography at the Children's Hospital of Boston showed a large mass in the right kidney, and a nephrectomy revealed a Wilms tumor. Postoperatively, the patient received 2,000 R to the abdomen through I0 by 15 cm portals, administered over three weeks with 250-kVp unit. Wilms tumor did not recur but nine years later the patient developed scoliosis, hypoplasia of the right iliac bone, and shortened right femoral neck with growth disturbance of the proximal femoral epiphysis. These abnormalities were attribflted to radiotherapy effects. A left femoral epiphysiodesis was performed in 1959 for discrepancy in length of the legs, In 1975, at 27 years of age, the patient was evaluated for rectal bleeding and tenesmus of six months' duration. Rectal examination revealed a large constricting mass. Biopsy and a Miles resection showed an adenocarcinoma of the rectum. He developed metastases in the.liver and lung, and obstruction of the left ureter. He died at 29 years of age. DISCUSSION Survivors of childhood neoplasia are at increased risk of another primary cancer, 2 possibly because of unusual host susceptibility, carcinogenic effects of prior cancer therapy, or both factors? The majority of second malignancies are sarcomas, leukemias, and other cancers usually found in children and young adults. Among epithelial tumors, carcinoma of the thyroid has been reported after radiation exposure during childhood? In our Patient and in Sabio's, adenocarcinoma of the large intestines developed 26 and 11 years, respectively, after abdominal radiotherapy for Wilms tumor. The complication has been rare but may increase in frequency in the future, particularly among patients who require intense treatments to cure Wilms tumor or another childhood cancer. Frederick P. Li,M.D. Clinical Studies Section National Cancer Institute 44 Binney St. Boston, MA 02115
recessively inherited vaginal atresia and its variable association with rectovaginal fistulas and postaxial polydactyly. Much later, Kaufman, 2 on the basis of a single additional case, suggested that cortgenital heart disease was another, occasional manifestation of the syndrome. In 1977, McKusick ~ proposed the term Kaufman syndrome. We felt that the importance of McKusick's contributions far outweighed that of Kaufman, and offered this new term before Kaufman syndrome had time to come into current use. In general, however, we support Dr. Heeht's plea. Let us hope that some international body will devise a more uniform terminology, as did the international group which adopted and later revised the nomenclature for skeletal dysplasias.4 Certainly, there are areas where uniformity would be helpful. For instance, we ought to agree whether it should be Wiedemann-Beckwith or Beckwith-Wiedemann. We should dispose with first names in eponyms (Robi n syndrome instead of Pierre Robin syndrome) and perhaps drop third names from triple eponyms, such as Charcot-Marie-Tooth. In some other areas, however, we may not yet be ready for uniformity. Which is more appropriate': Tetraphocomelia with cleft palate,. S-C syndrome, Roberts syndrome, or pseudothalidomide syndrome? Are we dealing with one or two syndromes? Opinions are still divided. An early decision in favor of one of these tel-ms may prove troublesome later. We believe that there is a legitimate place for the apparent chaos. In the early stages of syndrome delineation adherence to any standard system of nomenclature is often neither feasible nor desirable. Initial labels are often intentionally vague, to be :superseded by more definitive terms as more knowledge is gained. Gertrud Hurler called her syndrome "A type of multiple anomalies, mainly of the skeletal system. ''~ As more cases were recognized, Hurler disease seemed a suitable name. Attempts to get rid of the eponym resulted in gargoylism (descriptive but demeaning and therefore unacceptable today) and lipochondrodystrophy (misleading, since the stored material proved not to be a lipid). Correlation of biochemical, clinical and genetic studies led to McKusick's numerical classification, in which the disorder became mucopolysaccharidosis I, The discovery of the enzyme defect permitted coinage of the more specific (though not necessarily preferable) term a-L-iduronase deficiency, Hurler form.4 Syndrome terms will evolve, often for the better, sometimes for the worse and, as language in general, not always to the liking of the purists. Let us hope for some modest progress toward uniformity but realize that there is a legitimate place for diversity, and even for apparent chaos. Meinhard Robinow, M.D. Wright State University School of Medicine Department of Pediatrics Dayton, OH 45404 Anthony Shaw,, M.D. University of Virginia School of Medicine Department of Surgery Charlottesville, VA 22908 REFERENCES 1. Hecht FA: A common toothbrush for dysmorphology, J PED~A'r~.95:812, 1979.
Editorial correspondence
9 53
2.
Kaufman RL, Hartman AF, McAlister WH: Family studies in congenital heart disease. II. A syndrome of hydrometrocolpos, postaxial polydactyly and congenital heart disease, Birth Defects 8:85, 1972. 3. McKusick VA: The William Allen Memorial Lecture. Genetic nosology. Three approaches, Am J Hum Genet 3:105, 1978. 4. International Nomenclature of Constitutional Diseases of Bone, Revision--May 1977, Am J Med Genet 3:21, 1979. 5. Hurler G: Ober einen Typ multipler Abartungen, vorwiegend am Skelettsystem, Ztschr Kinderh 24:220, 1920.
PKU--hypothesis concerning failures of screening To the Editor. Several screening programs for phenylketonuria (PKU) in the United States have reported a 5 to 10% incidence of missed cases, most of which arepresumed to be due to the lack of a centralized laboratory? Hohzman et aF has postulated that some cases of PKU are missed because their blood phenylalanine concentration rises more slowly than usual after birth. I would like to propose a biochemical hypothesis to account for a portion of these missed cases. My premise is that a fetal phenylalanine hydroxylase enzyme can persist into neonatal life. Thus, a newborn infant with "classical" phenylketonuria and persistence of a fetal isozyme could have a screening test performed and be reported as normal because the enzyme keeps the blood phenylalanine at normal levels. When the fetal isozyme no longer functions, and if the infant has no "adult" phenylalanine hydroxylase, the blood phenylalanine would eventually rise. Unfortunately,9 by that time the child would have been discharged home with a normal test. Several investigators have shown the existence of phenylalanine hydroxylase isozymes ~ and modifiersr and Barranger et aP have reported the existence of a fetal isozyme, whidl would lend support to my hypothesis. It is also interesting to note that PKU cases are rarely missed in England, where screening occurs at a later date than in this country. Julian L. Berman, M.D. The Chicago Medical School 2020 West Ogden Ave. Chicago, IL 60612 REFERENCES 1. Sepe SJ, Levy HL, and Mount FW: An evaluation of routine follow-up blood screening of infants for phenylketonuria, N Engl J Med 300:606, 1979. 2. Holtzman NA, Mellits ED, and Kallman CN: Neonatal screening for phenylketonuria. II. Age dependence of initial phenylalanine in infants with PKU, Pediatrics 53:353, 1974. 3. Parker CE, Barranger J, Newhouse R, and Bessman S: Studies of the isozymes of phenylalanine hydroxylase in humans, Biochem Med 1"7:8, 1977.
9 54
Editorial correspondence
4.
Donlon J, and Kaufman S: Modification of the multiple forms of rat hepatic phenylalanine hydroxylase by in vitro phosphorylation, Biochem Biophys Res Commun 78:1011, 1977. 5. Barranger JA, Gelger PJ, Huzino A, and Bessman SP: Isozymes of phenylalanine hydroxylase. Science 175:903, 1972.
Simultaneous recovery of ampicillinsensitive and ampicillin-resistant H. influenzae from blood To the Editor: The simultaneous isolation of both ampicillin-sensitive and ampicillin-resistant Haemophilus influenzae from patients deserves special consideration by clinicians lreating infections if the disease progresses despite what appears to be adequate and appropriate therapy. Jubelirer and Yeager's repoW of two patients from whom ampicillin-sensitive H. influenzae were isolated from cerebrospinal fluid and ampicillin-resistant isolates were recovered from blood underscores the clinical significance of this observation. We recently have seen an adult patient from whose blood ampicillin-susceptible and ampicillin-resistant H. influenzae were isolated simultaneously. Pediatricians encounter bacteremia caused by H. influenzae more frequently than do physicians treating adults, and !t is particularly important that the heterogeneity of bacterial populations in regard to antibiotic susceptibility be appreciated in this context. The two strains of H. influenzae encountered in our patient were morphologically indistinguishable and were recognized only when rapid beta lactamase determinations and disc diffusion susceptibility tests~ differed. It behooves both the clinical microbiologist and the clinician to remember that a bacterial colony may not be representative of the potential genetic heterogeneity of the bacterial population as a whole. Recognition of bacterial subpopulations is dependent on variation in phenotypically recognizable characteristics. Detection of antibiotic-resistant subpopulations among morphologically indistinguishable colony types may be contingent on the chance testing of colonies which express susceptibility differences. In the face of treatment failure with seemingly appropriate drugs, reculture of infected sites is useful to detect population shifts in the predominant phenotype. If the specimen is unrepeatable or involves inadvisable invasive techniques, examination of additional representative colonies of the bacterial isolate for initially undetected antibiotic resistant subpopulations may be of value. David G. Beckwith, Ph.D. Clinical Microbiologist "Department of Pathology St. Luke's Hospital Bethlehem, PA 18015
The Journal of Pediatrics May 1980 REFERENCES
1. Jubelier DP, and Yeager AS: Simultaneous recovery of ampicillin-sensitive and ampicillin-resistant organisms in Haemophilus influenzae type b meningitis, J PEDIATR 95:415, i979. 2. NCCLS performance standards for antimicrobic disc susceptibility tests, ed 2, Vilianova, Pa., 1979, NCCLS, p 11.
Colon cancer after Wilms tumor To the Editor: Sabio et al 1 recently described a patient who developed adenocarcinoma of the colon after treatments for Wilms tumor. I Msh to report a second patient with the same sequence of multiple primary cancers. CASE REPORT
An abdominal mass was found in an 11-month-old boy in 1948. Intravenous pyelography at the Children's Hospital of Boston showed a large mass in the right kidney, and a nephrectomy revealed a Wilms tumor. Postoperatively, the patient received 2,000 R to the abdomen through I0 by 15 cm portals, administered over three weeks with 250-kVp unit. Wilms tumor did not recur but nine years later the patient developed scoliosis, hypoplasia of the right iliac bone, and shortened right femoral neck with growth disturbance of the proximal femoral epiphysis. These abnormalities were attribflted to radiotherapy effects. A left femoral epiphysiodesis was performed in 1959 for discrepancy in length of the legs, In 1975, at 27 years of age, the patient was evaluated for rectal bleeding and tenesmus of six months' duration. Rectal examination revealed a large constricting mass. Biopsy and a Miles resection showed an adenocarcinoma of the rectum. He developed metastases in the.liver and lung, and obstruction of the left ureter. He died at 29 years of age. DISCUSSION Survivors of childhood neoplasia are at increased risk of another primary cancer, 2 possibly because of unusual host susceptibility, carcinogenic effects of prior cancer therapy, or both factors? The majority of second malignancies are sarcomas, leukemias, and other cancers usually found in children and young adults. Among epithelial tumors, carcinoma of the thyroid has been reported after radiation exposure during childhood? In our Patient and in Sabio's, adenocarcinoma of the large intestines developed 26 and 11 years, respectively, after abdominal radiotherapy for Wilms tumor. The complication has been rare but may increase in frequency in the future, particularly among patients who require intense treatments to cure Wilms tumor or another childhood cancer. Frederick P. Li,M.D. Clinical Studies Section National Cancer Institute 44 Binney St. Boston, MA 02115