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Nesidioblastosis in Beckwith syndrome
Volume 86 Number 4
REFERENCES 1. Hollister DW, Rimoni, DL, Lackman RS~ Cohen AH, Reed WB, and Westin GW: The Winchester syndrome: A nonlysosomal connective tissue disease, J PEDIATR 84:70, 1974. 2. Winchester P, Grossman H, Lim WN, and Danes BS: A new acid mucopolysaccharidons with skeletal deformities simulating r h e u m a t o i d arthritis, A m J R o e n t g e n o l 106:121, 1969. 3. Brown SI, and Kuwalara T: Peripheral corneal opacities and skeletal deformities: a newly recognized acid mucopolysaccharidosis simulating rheumatoid arthritis, Arch Ophthalmol 83:667, 1970. 4. McKusick VA: Heritable disorders of connective tissue, ed 4, St. Louis, 1972, The CV Mosby Company, pp 627-629. 5. Ide H, a n d F i s h m a n WH: Dual localization of /3glucuronidase and acid phosphatase in lyosomes and in microsomes. II. Membrane associated enzymes, Histochemie 20:300, 1969. 6. Paigen K: The effect of mutation on the intracellular location of B-glucuronidase, Exp Cell Res 25:286, 1961. 7. G a n s c h o w R, and Paigen K: Separate genes determining the structure and intracellular location of hepatic glucuronidase Proc Nat Acad Sci 58:938, 1967. 8. Stumpf DA, Austin JH, Crocker AC, and LaFrance M: Mucopolysaccharidosis Type VI (Maroteaux-Lamy syndrome). I. Sulfatase B deficiency in tissues, Am J Dis Child 126:747, 1973. 9. Austin JH: Metachromatic leukodystrophy:XII Multiple sulfatase deficiency Arch Neurol 28:258, 1973. 10. Roy AB, and Trudinger PA: The biochemistry of inorganic compounds of sulphur, London, 1970, Cambridge University Press, pp 142-143. 11. Makita T, and Sandbom EB: Ultrastructural localization of sulfatase B in mitochondria of epithelial cells of the proximal convoluted tubules of the rat kidney, Experientia 27:187, 1971.
Repty
Letters to the Editor
6 47
represent a "disorder of mucopolysaccharide metabolism." In the second instance, Type VII mucopolysaccbaridosis, originally described by one of us (D. L. R.), is not a deficiency of fl-galactosidase. Rather, as originally reported, 3 this syndrome is characterized by a deficiency of fl-glucuronidase, an entirely distinct lysosomal enzyme. Since the Winchester syndrome is presumably inherited as an autosomal recessive disorder, we would certainly agree that an enzyme deficiency is likely. We are intrigued by Dr. Stumpf's hypothesis, yet we see no reason at this point to presume that a nonlysosomal hydrolytic enzyme might be responsible. Other hypotheses are tenable and some perhaps more attractive. Clarification of the biochemical pathophysiology in this disorder should lead to a rational search for the relevant enzyme deficiency.
David IV. Hollister, M.D. David L. Rimoin, M.D., Ph.D. UCLA School of Medicine Harbor General Hospital Campus 1000 W. Carson St. Torrance, Calif. 90509
REFERENCES 1.
Hollister DW, Rimoin DL, Lachman RS, Cohen AH, and Reed WB: The Winchester syndrome: A nonlysosomal connective tissue disease, J PEDIATR84:701, 1974. 2. McKusick VA: Heritable disorders of connective tissue, ed 4, St. Louis, 1972, The CV Mosby Company. 3. Sly WS, Quinton BA, McAlister WH, and Rimoin DL: Beta glucuronidase deficiency: Report of clinical, radiologic and biochemical features of a new mucopolysaccharidosi~s, J PEDIATR82:249, 1973.
Nesidioblastosis in Beckwith syndrome
To the Editor: We thank Dr. Stumpf for his interest in our paper, 1 but fear he suffers from several erroneous assumptions. In the first instance, we did not "dismiss the notion that [the Winchester Syndrome] is a disorder of mucopolysaccharide metabolism." Rather, we pointed out that this disorder is not a lysosomal storage disease. This statement is equivalent to saying that there exists no defect in intralysosomal degradation leading to lysosomal engorgement, and the deleterious effects thereof. Since all of the classified mucopolysaccharidoSes 2 are characterized by intralysosomal storage of mucopolysaccharide and excessive mucopolysaccharidnria, and these are absent in the Winchester syndrome, clearly this syndrome is not a mucopolysaccharidosis. Nor can it be classified as another sort of lysosomal storage disease. These statements do not imply that the synthesis, structure, distribution, or function of mucopolysaccharide are normal, a defect in any of which might
To the Editor: We have recently observed the Beckwith-Wiedemann syndrome in a newborn infant who died at 18 days of age and had all major pathologic findings at autopsy. The purpose of this communication is to call attention to the histology of the pancreas, which presented an anomalous mixture of insular and acinar components associated with hypertrophy and hyperplasia of the islets. Insular cells were not always found in well-defined islets, but irregularly mingled with acinar and ductal tissue (Fig. 1). This histologic feature suggests the process called nesidioblastosis of the pancreas. This abnormality without pancreatic hyperplasia was described previously in children with hypoglycemia 1' 2 and in adults with sulfonylurea-treated diabetes3; histologic features of nesidioblastosis in association with pancreatic hyperplasia have been reported by Roe and as-
648
Letters to the Editor
The Journal of Pediatrics April19 7 5
Fig. 1. Photomicrograph of the pancreas showing insular cells irregularly mingled with acinar and ductal tissue. (Hematoxylin-eosin stain; x 130.)
sociates 4 in a newborn infant presenting with Beckwith syndrome. Nesidioblastosis in the Beckwith syndrome may represent a persistent neoformation of islet cells from ductular elements of e x o c r i n e pancreas. This process, like t h e persistent nephronogenesis also observed in our patient, represents another aspect of the excessive cell proliferation which characterizes the histology of the syndrome.
F. Dammacco, M.D. F. Carnevale, M.D. Institute of Clinical Pediatrics M. Albrizio, M.D. Institute of Pathological Anatomy University of Bari Policlinico Piazza Giulio Cesare 70124 -Bari, Italy
REFERENCES 1.
2.
3. 4.
Yakovac MD, Baker L, and H u m m e l e r K: Beta cell nesidioblastosis in idiopathic hypoglycemia of infancy, J PEOIATR79:226, 1971. Brown, RE, and Young RB: A possible role for the exocrine pancreas in the pathogenesis of neonatal leucinesensitive hypoglycemia, Am J Dig Dis 15:65, 1970. Bloodworth JMB Jr: Morphologic changes associated with sulfonylurea therapy, Metabolism 12:287, 1963. Roe TF, Kershnar AK, Weitzmann J J, and Madrigal LS: Beckwith's syndrome with extreme organ hyperplasia, Pediatrics 52:372, 1973.
Source of renal vein renin questioned To the Editor: I would like to refer to Bennett and co-workers 1 article "Juvenile hypertension caused by over production of renin within a renal segment." This child had a markedly elevated urinary aldosterone and plasma renin but renal vein renin activity was equal and normal on both sides on renal vein catheterization. Subsequently at laparotomy a markedly increased renin activity was demonstrated in blood from the lower pole of the right kidney and removal of this cured the hypertension. The explanation of the normal renal vein catheterization study was that the normal upper pole drainage diluted the abnormal lower pole drainage, but this explanation does not make sense unless one assumes the upper pole renin was quite a bit decreased or that the venous return from the normal area was of much greater volume. However the secretion of renin was enough to raise the general plasma level markedly so it seems difficult to see how dilution could normalize the renal vein renin. I would suggest the explanation that streaming of venous blood from different renal segments occurs within the renal vein and that in fact at catheterization the sample obtained just happened to be all upper pole blood. I have no proof of this but at least it is an hypothesis, whereas the reason given in the article ignores the problem. B. M. Symons, M.B.B.S., D.T.M.&H. Child Guidance Clinic Brisbane St. Surly Hills, N.S. Be. 2010 Australia
REFERENCES 1. Hollister DW, Rimoni, DL, Lackman RS~ Cohen AH, Reed WB, and Westin GW: The Winchester syndrome: A nonlysosomal connective tissue disease, J PEDIATR 84:70, 1974. 2. Winchester P, Grossman H, Lim WN, and Danes BS: A new acid mucopolysaccharidons with skeletal deformities simulating r h e u m a t o i d arthritis, A m J R o e n t g e n o l 106:121, 1969. 3. Brown SI, and Kuwalara T: Peripheral corneal opacities and skeletal deformities: a newly recognized acid mucopolysaccharidosis simulating rheumatoid arthritis, Arch Ophthalmol 83:667, 1970. 4. McKusick VA: Heritable disorders of connective tissue, ed 4, St. Louis, 1972, The CV Mosby Company, pp 627-629. 5. Ide H, a n d F i s h m a n WH: Dual localization of /3glucuronidase and acid phosphatase in lyosomes and in microsomes. II. Membrane associated enzymes, Histochemie 20:300, 1969. 6. Paigen K: The effect of mutation on the intracellular location of B-glucuronidase, Exp Cell Res 25:286, 1961. 7. G a n s c h o w R, and Paigen K: Separate genes determining the structure and intracellular location of hepatic glucuronidase Proc Nat Acad Sci 58:938, 1967. 8. Stumpf DA, Austin JH, Crocker AC, and LaFrance M: Mucopolysaccharidosis Type VI (Maroteaux-Lamy syndrome). I. Sulfatase B deficiency in tissues, Am J Dis Child 126:747, 1973. 9. Austin JH: Metachromatic leukodystrophy:XII Multiple sulfatase deficiency Arch Neurol 28:258, 1973. 10. Roy AB, and Trudinger PA: The biochemistry of inorganic compounds of sulphur, London, 1970, Cambridge University Press, pp 142-143. 11. Makita T, and Sandbom EB: Ultrastructural localization of sulfatase B in mitochondria of epithelial cells of the proximal convoluted tubules of the rat kidney, Experientia 27:187, 1971.
Repty
Letters to the Editor
6 47
represent a "disorder of mucopolysaccharide metabolism." In the second instance, Type VII mucopolysaccbaridosis, originally described by one of us (D. L. R.), is not a deficiency of fl-galactosidase. Rather, as originally reported, 3 this syndrome is characterized by a deficiency of fl-glucuronidase, an entirely distinct lysosomal enzyme. Since the Winchester syndrome is presumably inherited as an autosomal recessive disorder, we would certainly agree that an enzyme deficiency is likely. We are intrigued by Dr. Stumpf's hypothesis, yet we see no reason at this point to presume that a nonlysosomal hydrolytic enzyme might be responsible. Other hypotheses are tenable and some perhaps more attractive. Clarification of the biochemical pathophysiology in this disorder should lead to a rational search for the relevant enzyme deficiency.
David IV. Hollister, M.D. David L. Rimoin, M.D., Ph.D. UCLA School of Medicine Harbor General Hospital Campus 1000 W. Carson St. Torrance, Calif. 90509
REFERENCES 1.
Hollister DW, Rimoin DL, Lachman RS, Cohen AH, and Reed WB: The Winchester syndrome: A nonlysosomal connective tissue disease, J PEDIATR84:701, 1974. 2. McKusick VA: Heritable disorders of connective tissue, ed 4, St. Louis, 1972, The CV Mosby Company. 3. Sly WS, Quinton BA, McAlister WH, and Rimoin DL: Beta glucuronidase deficiency: Report of clinical, radiologic and biochemical features of a new mucopolysaccharidosi~s, J PEDIATR82:249, 1973.
Nesidioblastosis in Beckwith syndrome
To the Editor: We thank Dr. Stumpf for his interest in our paper, 1 but fear he suffers from several erroneous assumptions. In the first instance, we did not "dismiss the notion that [the Winchester Syndrome] is a disorder of mucopolysaccharide metabolism." Rather, we pointed out that this disorder is not a lysosomal storage disease. This statement is equivalent to saying that there exists no defect in intralysosomal degradation leading to lysosomal engorgement, and the deleterious effects thereof. Since all of the classified mucopolysaccharidoSes 2 are characterized by intralysosomal storage of mucopolysaccharide and excessive mucopolysaccharidnria, and these are absent in the Winchester syndrome, clearly this syndrome is not a mucopolysaccharidosis. Nor can it be classified as another sort of lysosomal storage disease. These statements do not imply that the synthesis, structure, distribution, or function of mucopolysaccharide are normal, a defect in any of which might
To the Editor: We have recently observed the Beckwith-Wiedemann syndrome in a newborn infant who died at 18 days of age and had all major pathologic findings at autopsy. The purpose of this communication is to call attention to the histology of the pancreas, which presented an anomalous mixture of insular and acinar components associated with hypertrophy and hyperplasia of the islets. Insular cells were not always found in well-defined islets, but irregularly mingled with acinar and ductal tissue (Fig. 1). This histologic feature suggests the process called nesidioblastosis of the pancreas. This abnormality without pancreatic hyperplasia was described previously in children with hypoglycemia 1' 2 and in adults with sulfonylurea-treated diabetes3; histologic features of nesidioblastosis in association with pancreatic hyperplasia have been reported by Roe and as-
648
Letters to the Editor
The Journal of Pediatrics April19 7 5
Fig. 1. Photomicrograph of the pancreas showing insular cells irregularly mingled with acinar and ductal tissue. (Hematoxylin-eosin stain; x 130.)
sociates 4 in a newborn infant presenting with Beckwith syndrome. Nesidioblastosis in the Beckwith syndrome may represent a persistent neoformation of islet cells from ductular elements of e x o c r i n e pancreas. This process, like t h e persistent nephronogenesis also observed in our patient, represents another aspect of the excessive cell proliferation which characterizes the histology of the syndrome.
F. Dammacco, M.D. F. Carnevale, M.D. Institute of Clinical Pediatrics M. Albrizio, M.D. Institute of Pathological Anatomy University of Bari Policlinico Piazza Giulio Cesare 70124 -Bari, Italy
REFERENCES 1.
2.
3. 4.
Yakovac MD, Baker L, and H u m m e l e r K: Beta cell nesidioblastosis in idiopathic hypoglycemia of infancy, J PEOIATR79:226, 1971. Brown, RE, and Young RB: A possible role for the exocrine pancreas in the pathogenesis of neonatal leucinesensitive hypoglycemia, Am J Dig Dis 15:65, 1970. Bloodworth JMB Jr: Morphologic changes associated with sulfonylurea therapy, Metabolism 12:287, 1963. Roe TF, Kershnar AK, Weitzmann J J, and Madrigal LS: Beckwith's syndrome with extreme organ hyperplasia, Pediatrics 52:372, 1973.
Source of renal vein renin questioned To the Editor: I would like to refer to Bennett and co-workers 1 article "Juvenile hypertension caused by over production of renin within a renal segment." This child had a markedly elevated urinary aldosterone and plasma renin but renal vein renin activity was equal and normal on both sides on renal vein catheterization. Subsequently at laparotomy a markedly increased renin activity was demonstrated in blood from the lower pole of the right kidney and removal of this cured the hypertension. The explanation of the normal renal vein catheterization study was that the normal upper pole drainage diluted the abnormal lower pole drainage, but this explanation does not make sense unless one assumes the upper pole renin was quite a bit decreased or that the venous return from the normal area was of much greater volume. However the secretion of renin was enough to raise the general plasma level markedly so it seems difficult to see how dilution could normalize the renal vein renin. I would suggest the explanation that streaming of venous blood from different renal segments occurs within the renal vein and that in fact at catheterization the sample obtained just happened to be all upper pole blood. I have no proof of this but at least it is an hypothesis, whereas the reason given in the article ignores the problem. B. M. Symons, M.B.B.S., D.T.M.&H. Child Guidance Clinic Brisbane St. Surly Hills, N.S. Be. 2010 Australia