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Evaluation of severe hypospadias
THE JOURNAL OF PEDIATRICS VOLUME 133, NUMBER I
REFERENCES 1.
Weinzimer SA. Stanley CA. Berry GT. Yudkoff M. Tuchmann M. Thornton PS. A syndrome of congenital hyperinsulinism and hyperammonemia. J Pediatr 1997:130:661-4. 2. Sann L. Dellomonica C. Hyperammonemia in hypoglycemic preterm neonates. Bioi Neonate 1983:44:49-53. 3. Krebs HA. Lund P. Stubb M. Interrelations between gluconeogenesis and urea synthesis. In: Hanson H. Mehlman J. editors. Gluconeogenesis: its regulation in mammalian species. New York: Wiley: 1976. p. 269-91. 4. Mestyan J. Saltes G. Schultz K. Horwath M. Hyperaminoacidemia due to accumulation of gluconeogenic amino acid precursors in hypoglycemic small-fordate infants. J Pediatr 1975:87:409-14.
Reply To the EiJilvr: Dr. Sann's report of elevated blood ammonium in preterm neonates with hypoglycemia during the first few hours after birth is obviously of great interest now that we and others have recognized the hyperinsulinismlhyperammonemia syndrome.1.2 In 1983 Sann et al. 3 speculated that the disturbance in ammonia that they found in neonates reflected a hepatic response to hypoglycemia despite the fact that hyperammonemia is not a usual concomitant of hypoglycemia. This is an opportune time for further investigation of their observations; we would like to suggest two possibilities for consideration. One is that hyperammonemia in some hypoglycemic neonates might be a consequence of the "normal" delay in development of the activity of carnitine palmitoyl transferase1. 4 one of the enzymes required for hepatic fatty acid oxidation and ketogenesis. because hyperammonemia is known to occur at times of hypoglycemia in children who have genetic defects of fatty acid oxidation. The second possibility to consider is whether the hyperammonemia might actually be associated with hyperinsulinism. because there is evidence that hypoglycemia in infants who have perinatal asphyxia or are small for gestational age may be caused by hyperinsulinism. 5 One could speculate that the infants studied by Dr. Sann might represent some relatively common. acquired form of transient hyperinsulinismlhyperammonemia and that the cause of this transient disorder might
LETTERS
be related to the genetic syndrome of hyperinsulinism and hyperammonemia that we reported. A report describing the molecular basis of the disorder in our patients is now in preparation.
Stuart Alan Wemzinur, MD Charlu A. Stanley, MD Di"i.,wll of Endocrmolo..lJy/DiLlbde., ChifJren;' HO.lpiJal of PhibJelphiLl Ulli"er"ity of Peml.ly/"aniLl Schoolol Medicille PhiladelphiLl, PA 19104-9786 9/J5/880JO
REFERENCES 1. Weinzimer SA. Stanley CA. Berry GT. Yudkoff M. Tuchmann M. Thornton PS. A syndrome of congenital hyperinsulinism and hyperammonemia. J Pediatr 1997:130:661-4. 2. Zammarchi E. Filippi L. Novembre E. Donati MA. Biochemical evaluation of a patient with a familial form of leucinesensitive hypoglycemia and concomitant hyperammonemia. Metab 1996:45:95760. 3. Sann L. Dellamonica C. Hyperammonemia in hypoglycemic preterm neonates. Bioi Neonate 1983:44:49-53. 4. Thumelin S. Esser V, Charvy D. Kolodziej M. Zammit VA. McGarry D. et al. Expression of liver camitine palmitoyltransferase I and II genes during development in the rat. Biochem J 1994: 300:583-7. 5. Collins JE. Leonard JV, Teale D. Marks V. Williams OM. Kennedy CR. et al. Hyperinsulinaemic hypoglycaemia in small for dates babies. Arch Dis Child 1990:65:1118-20.
A role for cytokines in toxic shock syndrome? To the EiJitor: The serum cytokine profile reported by Van Lierde et al.I in a 15-month-old child with toxic shock syndrome without rash is important evidence of a possible link between hemorrhagic shock and encephalopathy (HSE). toxic shock syndrome. and heatstroke (HS). There is convincing clinical. biochemical. and pathologic evidence that HSE and HS may be closely related. if not identical. conditions.2.3 The hyperthermia. shock. multiple organ dysfunction syndrome. disseminated intravascular coagulopathy. and brain edema with punctate hemorrhages are common features to HSE and HS. Serum cytokine profiles among heatstroke victims during the pilgrimage
to Makkah in Saudi Arabia 4 •5 show increased levels of the same cytokines found by Van Lierde et al. in their case: tumor necrosis factor-a. interleukin-6" and interferon-yo We believe that hyperthermia may be the instigator in the subsequent cascade that results in multiple organ dysfunction syndrome. 6 Further studies may help to clarifY the role pyrogenic cytokines play in toxic shock syndrome. HSE. and HS.
Enrique Cha"e,I-Carballo, MD Abderrezal.: &lIIchama, MD Department of Neuro.,clcnce., Departnunt ofMedicme Kin.lJ Fai..al SpeciLlwt Ho.lpltal and Re.learch Centre Riyadh, Saudi ArabiLl 9/J5/880J2
REFERENCES 1. Van Lierde S. Van Leeuwen WJ. Ceuppens J. Cornette L. Goubau P. Van Eldere J. Toxic shock syndrome without rash in a young child: Link with syndrome of hemorrhagic shock and encephalopathy? J Pediatr 1997;131:130-4. 2. Levin M. Pincott JR. Hjelm M. Taylor F. Kay J. Holzel H. et al. Hemorrhagic shock and encephalopathy: clinical. pathologic. and biochemical features. J Pediatr 1989:114:194-203. 3. Chaves-Carballo E. Montes JE. Nelson WB. Chrenka BA. Hemorrhagic shock and encephalopathy: clinical definition of a catastrophic syndrome in infants. Am J Dis Child 1990:144:1079-82. 4. Bouchama A. Parhar RS. el- Yazigi A. Sheth K. AI-Sedairy S. Endotoxemia and release of tumor necrosis factor and interleukin 1 alpha in acute heatstroke. J Appl PhysioI1991:70:2640-4. 5. Bouchama A. AI-Sedairy S. Siddiqui S. Shail E. Rezeig M. Elevated pyrogenic cytokines in heatstroke. Chest 1993: 104: 1498-502. 6. Chaves-Carballo E. Bouchama A. Fever. heatstroke. and hemorrhagic shock and encephalopathy. J Child Neurol (accepted for publication).
Evaluation of severe hypospadias To the EiJilvr: In their editorial commentary on the article regarding the etiologic classification of severe hypospadias by Albers et al.. 1 Smith and Wacksman 2 state that. ..... bilateral descent of the testes into a well differentiated scrotum is strong evi-
169
LETTERS
THE JOURNAL OF PEDIATRICS JULY
dence that androgen action is largely intact and that the hypospadias is very likely to have been caused by a non-hormonal. idiopathic process." This interpretation is based on the observation that of two patients with partial androgen resistance and one with 5-Clketo-reductase deficiency, only one had bilateral descent. The patient with 5-Clketo-reductase deficiency had unilateral cryptorchidism. Because one of two patients with partial androgen insensitivity had bilateral descent, it can hardly be said that such an occurrence is strong evidence of normal androgen action. Such an interpretation can lead to delay in diagnosis and unpleasant surprises at adolescence. I have recently seen three brothers of native Indian descent with Dr. Javier Saavedra in Bolivia who emphasize the point that normal testicular descent is consistent with substantial androgen insensitivity. They had pseudovaginal penoscrotal hypospadias with normal scrotal formation and testicular development. The two older boys had 15 to 20 cc testes of normal consistency and only came to diagnosis when they refused to return to school because of impressive breast development with the onset of adolescence. The younger boy had normal prepubertal (1.5 to 2 cc) testes in the scrotum. Bilateral descended testes in a wellformed scrotum does not ensure intact androgen action. Severe hypospadias must be evaluated genetically and biochemically in such situations.
Arlan L. ROJenhloom, MD Di.,tingui.,hed Service Pro/e.!.!or Emeritu.,
170
Divi.,wn 0/ Endocrinolo/IY Department 0/ Pediatric.! UniJ'mity of FloriJa College 0/ Medicine GaUu.JJ'iLie, FL 32610-0296 9/35/88542
REFERENCES 1. Albers N, Ulrichs C, Gliier S, Hiort 0, Sinnecker GHG, Mildenberger H, et al. Etiologic classification of severe hypospadias: implications for prognosis and management. J Pediatr 1997;131:386-92. 2. Smith EP, Wacksman J. Evaluation of severe hypospadias. J Pediatr 1997;
tient with well-differentiated scrotum, bilaterally descended testes, and adequate phallic size is "very unlikely" to have a definable cause given the existing diagnostic tests available. In these individuals, after a normal 46 XY karyotype and ultrasound, there is no uncertainty about sex assignment, and therefore the urgency for further testing is abated and a judgment can be made whether further testing is warranted given the resources available.
Eric R Smith, MD Jef/rey Wack.iman, MD Divi.Jwn 0/ Endocrinology Divi.,wn 0/ Urology Department 0/ Pediatric.! UniJ'erJily 0/ Cincinnati Medical Center Cincinnati, OH 45229-3039 9/35/8854:1
131:344-6.
Reply To tbe EiJitor: We acknowledge Dr. Rosenbloom's concerns regarding the possible consequences regarding delayed diagnostic testing of patients with severe hypospadias. We do not agree completely with all of his comments, however. Dr. Rosenbloom suggests that our editorial l conveys the conclusion that bilateral descent of the testes is "strong evidence of normal androgen action." More precisely, our editorial indicates "bilateral descent of the testes into a well differentiated scrotum is strong evidence that androgen action is largely intact and the hypospadias is very likely to have been caused by a non-hormonal idiopathic process." Our primary point was that on the basis of the review of Albers et al. 2 and other similar recent studies, 3 a pa-
1998
REFERENCES Smith EP, Wacksman J Evaluation of severe hypospadias. J Pediatr 1997;131: 344-6. 2. Albers N, Ulfichs C, Gliier S, Hiort 0, Sinnecker GHG, Mildenberger H, et al. Etiologic classification of severe hypospadias: implications for prognosis and management. J Pediatr 1997; 131: 386-92. 3. Sinnecker GHG, Hiort 0, Dibbelt L, Dorr HG, Haub H, Hemrich U, et al. Phenotypic classification of male pseudohermaphroditism due to steroid 5-
REFERENCES 1.
Weinzimer SA. Stanley CA. Berry GT. Yudkoff M. Tuchmann M. Thornton PS. A syndrome of congenital hyperinsulinism and hyperammonemia. J Pediatr 1997:130:661-4. 2. Sann L. Dellomonica C. Hyperammonemia in hypoglycemic preterm neonates. Bioi Neonate 1983:44:49-53. 3. Krebs HA. Lund P. Stubb M. Interrelations between gluconeogenesis and urea synthesis. In: Hanson H. Mehlman J. editors. Gluconeogenesis: its regulation in mammalian species. New York: Wiley: 1976. p. 269-91. 4. Mestyan J. Saltes G. Schultz K. Horwath M. Hyperaminoacidemia due to accumulation of gluconeogenic amino acid precursors in hypoglycemic small-fordate infants. J Pediatr 1975:87:409-14.
Reply To the EiJilvr: Dr. Sann's report of elevated blood ammonium in preterm neonates with hypoglycemia during the first few hours after birth is obviously of great interest now that we and others have recognized the hyperinsulinismlhyperammonemia syndrome.1.2 In 1983 Sann et al. 3 speculated that the disturbance in ammonia that they found in neonates reflected a hepatic response to hypoglycemia despite the fact that hyperammonemia is not a usual concomitant of hypoglycemia. This is an opportune time for further investigation of their observations; we would like to suggest two possibilities for consideration. One is that hyperammonemia in some hypoglycemic neonates might be a consequence of the "normal" delay in development of the activity of carnitine palmitoyl transferase1. 4 one of the enzymes required for hepatic fatty acid oxidation and ketogenesis. because hyperammonemia is known to occur at times of hypoglycemia in children who have genetic defects of fatty acid oxidation. The second possibility to consider is whether the hyperammonemia might actually be associated with hyperinsulinism. because there is evidence that hypoglycemia in infants who have perinatal asphyxia or are small for gestational age may be caused by hyperinsulinism. 5 One could speculate that the infants studied by Dr. Sann might represent some relatively common. acquired form of transient hyperinsulinismlhyperammonemia and that the cause of this transient disorder might
LETTERS
be related to the genetic syndrome of hyperinsulinism and hyperammonemia that we reported. A report describing the molecular basis of the disorder in our patients is now in preparation.
Stuart Alan Wemzinur, MD Charlu A. Stanley, MD Di"i.,wll of Endocrmolo..lJy/DiLlbde., ChifJren;' HO.lpiJal of PhibJelphiLl Ulli"er"ity of Peml.ly/"aniLl Schoolol Medicille PhiladelphiLl, PA 19104-9786 9/J5/880JO
REFERENCES 1. Weinzimer SA. Stanley CA. Berry GT. Yudkoff M. Tuchmann M. Thornton PS. A syndrome of congenital hyperinsulinism and hyperammonemia. J Pediatr 1997:130:661-4. 2. Zammarchi E. Filippi L. Novembre E. Donati MA. Biochemical evaluation of a patient with a familial form of leucinesensitive hypoglycemia and concomitant hyperammonemia. Metab 1996:45:95760. 3. Sann L. Dellamonica C. Hyperammonemia in hypoglycemic preterm neonates. Bioi Neonate 1983:44:49-53. 4. Thumelin S. Esser V, Charvy D. Kolodziej M. Zammit VA. McGarry D. et al. Expression of liver camitine palmitoyltransferase I and II genes during development in the rat. Biochem J 1994: 300:583-7. 5. Collins JE. Leonard JV, Teale D. Marks V. Williams OM. Kennedy CR. et al. Hyperinsulinaemic hypoglycaemia in small for dates babies. Arch Dis Child 1990:65:1118-20.
A role for cytokines in toxic shock syndrome? To the EiJitor: The serum cytokine profile reported by Van Lierde et al.I in a 15-month-old child with toxic shock syndrome without rash is important evidence of a possible link between hemorrhagic shock and encephalopathy (HSE). toxic shock syndrome. and heatstroke (HS). There is convincing clinical. biochemical. and pathologic evidence that HSE and HS may be closely related. if not identical. conditions.2.3 The hyperthermia. shock. multiple organ dysfunction syndrome. disseminated intravascular coagulopathy. and brain edema with punctate hemorrhages are common features to HSE and HS. Serum cytokine profiles among heatstroke victims during the pilgrimage
to Makkah in Saudi Arabia 4 •5 show increased levels of the same cytokines found by Van Lierde et al. in their case: tumor necrosis factor-a. interleukin-6" and interferon-yo We believe that hyperthermia may be the instigator in the subsequent cascade that results in multiple organ dysfunction syndrome. 6 Further studies may help to clarifY the role pyrogenic cytokines play in toxic shock syndrome. HSE. and HS.
Enrique Cha"e,I-Carballo, MD Abderrezal.: &lIIchama, MD Department of Neuro.,clcnce., Departnunt ofMedicme Kin.lJ Fai..al SpeciLlwt Ho.lpltal and Re.learch Centre Riyadh, Saudi ArabiLl 9/J5/880J2
REFERENCES 1. Van Lierde S. Van Leeuwen WJ. Ceuppens J. Cornette L. Goubau P. Van Eldere J. Toxic shock syndrome without rash in a young child: Link with syndrome of hemorrhagic shock and encephalopathy? J Pediatr 1997;131:130-4. 2. Levin M. Pincott JR. Hjelm M. Taylor F. Kay J. Holzel H. et al. Hemorrhagic shock and encephalopathy: clinical. pathologic. and biochemical features. J Pediatr 1989:114:194-203. 3. Chaves-Carballo E. Montes JE. Nelson WB. Chrenka BA. Hemorrhagic shock and encephalopathy: clinical definition of a catastrophic syndrome in infants. Am J Dis Child 1990:144:1079-82. 4. Bouchama A. Parhar RS. el- Yazigi A. Sheth K. AI-Sedairy S. Endotoxemia and release of tumor necrosis factor and interleukin 1 alpha in acute heatstroke. J Appl PhysioI1991:70:2640-4. 5. Bouchama A. AI-Sedairy S. Siddiqui S. Shail E. Rezeig M. Elevated pyrogenic cytokines in heatstroke. Chest 1993: 104: 1498-502. 6. Chaves-Carballo E. Bouchama A. Fever. heatstroke. and hemorrhagic shock and encephalopathy. J Child Neurol (accepted for publication).
Evaluation of severe hypospadias To the EiJilvr: In their editorial commentary on the article regarding the etiologic classification of severe hypospadias by Albers et al.. 1 Smith and Wacksman 2 state that. ..... bilateral descent of the testes into a well differentiated scrotum is strong evi-
169
LETTERS
THE JOURNAL OF PEDIATRICS JULY
dence that androgen action is largely intact and that the hypospadias is very likely to have been caused by a non-hormonal. idiopathic process." This interpretation is based on the observation that of two patients with partial androgen resistance and one with 5-Clketo-reductase deficiency, only one had bilateral descent. The patient with 5-Clketo-reductase deficiency had unilateral cryptorchidism. Because one of two patients with partial androgen insensitivity had bilateral descent, it can hardly be said that such an occurrence is strong evidence of normal androgen action. Such an interpretation can lead to delay in diagnosis and unpleasant surprises at adolescence. I have recently seen three brothers of native Indian descent with Dr. Javier Saavedra in Bolivia who emphasize the point that normal testicular descent is consistent with substantial androgen insensitivity. They had pseudovaginal penoscrotal hypospadias with normal scrotal formation and testicular development. The two older boys had 15 to 20 cc testes of normal consistency and only came to diagnosis when they refused to return to school because of impressive breast development with the onset of adolescence. The younger boy had normal prepubertal (1.5 to 2 cc) testes in the scrotum. Bilateral descended testes in a wellformed scrotum does not ensure intact androgen action. Severe hypospadias must be evaluated genetically and biochemically in such situations.
Arlan L. ROJenhloom, MD Di.,tingui.,hed Service Pro/e.!.!or Emeritu.,
170
Divi.,wn 0/ Endocrinolo/IY Department 0/ Pediatric.! UniJ'mity of FloriJa College 0/ Medicine GaUu.JJ'iLie, FL 32610-0296 9/35/88542
REFERENCES 1. Albers N, Ulrichs C, Gliier S, Hiort 0, Sinnecker GHG, Mildenberger H, et al. Etiologic classification of severe hypospadias: implications for prognosis and management. J Pediatr 1997;131:386-92. 2. Smith EP, Wacksman J. Evaluation of severe hypospadias. J Pediatr 1997;
tient with well-differentiated scrotum, bilaterally descended testes, and adequate phallic size is "very unlikely" to have a definable cause given the existing diagnostic tests available. In these individuals, after a normal 46 XY karyotype and ultrasound, there is no uncertainty about sex assignment, and therefore the urgency for further testing is abated and a judgment can be made whether further testing is warranted given the resources available.
Eric R Smith, MD Jef/rey Wack.iman, MD Divi.Jwn 0/ Endocrinology Divi.,wn 0/ Urology Department 0/ Pediatric.! UniJ'erJily 0/ Cincinnati Medical Center Cincinnati, OH 45229-3039 9/35/8854:1
131:344-6.
Reply To tbe EiJitor: We acknowledge Dr. Rosenbloom's concerns regarding the possible consequences regarding delayed diagnostic testing of patients with severe hypospadias. We do not agree completely with all of his comments, however. Dr. Rosenbloom suggests that our editorial l conveys the conclusion that bilateral descent of the testes is "strong evidence of normal androgen action." More precisely, our editorial indicates "bilateral descent of the testes into a well differentiated scrotum is strong evidence that androgen action is largely intact and the hypospadias is very likely to have been caused by a non-hormonal idiopathic process." Our primary point was that on the basis of the review of Albers et al. 2 and other similar recent studies, 3 a pa-
1998
REFERENCES Smith EP, Wacksman J Evaluation of severe hypospadias. J Pediatr 1997;131: 344-6. 2. Albers N, Ulfichs C, Gliier S, Hiort 0, Sinnecker GHG, Mildenberger H, et al. Etiologic classification of severe hypospadias: implications for prognosis and management. J Pediatr 1997; 131: 386-92. 3. Sinnecker GHG, Hiort 0, Dibbelt L, Dorr HG, Haub H, Hemrich U, et al. Phenotypic classification of male pseudohermaphroditism due to steroid 5-