Volume 95 Number 1
3.
Editorial correspondence
Glaser B, and Smith JL: Leukaemic glaucoma, Br Ophthalmol 50:92, 1966.
Cutis marmorata telangiectatica congenita and neonatal ascites To the Editor: It was with great interest and appreciation that we read the article by South and Jacobs 1 recently published in Tr~E JOURNAL. However, none of the patients reported had any evidence of neonatal liver disease.
15 7
its presence in a patient with CMTC is curious enough that it should be added to the list of possible associated abnormalities. Robert B. Schuhz, M.D. 3939 Hollywood Bird, Hollywood, FL 33021 Samuel Kocos)~is, M.D. Yale University School of Medicine 333 Cedar St. New Haven, CT 06510 REFERENCE
1.
South DA: Cutis marmorata telangiectatica congenita, J PrD1ATR 93:944, 1978.
CASE REPORT
A female infant, born at our institution with neonatal ascites, cutis marmorata telangiectatica congenita (CMTC), and subcutaneous atrophy, was subsequently evaluated at Yale-New Haven Medical Center, Just prior tO delivery of this infant a pelvic sonogram was performed on the mother in anticipation o f possible cephalopelvic disproportion. The sonogram demonstrated a large mass at the level of t h e fetal abdomen. A n intrauterine gastrointestinal series, performed by instillation of sterile barium within the amniotic cavity, revealed normal GI architecture but the presence of ascites. The infant was delivered by cesarean section and the ascites was confirmed. Detailed study both at our institution and at Yale-New Haven Hospital failed to reveal the etiology of the ascites. Histologic examination of cord and placenta was normal. Serum thyroxine was 8.0 /~g/dl. Urine for cytomegalovirus was negative. The serum rubella titer was negative. A urine genetic screen was normal. Liver-spleen scan and bone marrow were normal, The hepatitis B-associated antigen and antibody were negative, and the alpha~-antitrypsin level was 193 mg/dl. Ultrasound disclosed diffuse increase in echoes throughout the liver, consistent with a pathologic hepatocellular process. Liver biopsy revealed mild increase in parenchymal iron but was otherwise normal. The VDRL was negative. Hepatosplenomegaly persisted for the first 4 months of life. SGOT values were elevated' during the first four months of life. A skin biopsy was consistent with CMTC. A computerized tomographic scan o f the head was normal. A barium swallow failed to reveal the presence of esophageal varices. At 3 months Of age quantitative immunoglobulin studies revealed the IgG to be 140 mg/dl and the IgA, 14 mg/dl; IgM was normal. The child is now eight months of age and has persistent CMTC with subcutaneous atrophy over both malar areas. The child has no neurologic deficits and has not experienced any unusual infections. DISCUSSION We have been unable to find any other cases of ascites in association with this syndrome or with other associated syndromes involving hemangiomatous malformations. This finding of ascites and the abnormal hepatic enzymes might suggest that this infant did in fact have an intrauterine infection which is not necessarily organ specific but which has an effect on the vascular system. Perhaps the ascites was purely coincidental, but
Impairment of immunity in children with intrauterine growth retardation To the Editor: The recent report of Ferguson I confirms earlier studies by us ~. and by two other groups ~. ~ demonstrating persistence of impairment of cell-mediated immunity in children with fetal growth retardation. A serious limitation of Ferguson's study is the small size and skewed nature of the sample populations examined. The conclusions on prolonged impairment of cellular immunity are based on observations on only eight children with a wide age range; the exact ages of the eight subjects are not stated. The percentage of rosetting T lymphocytes was significantly reduced in children with intrauterine growth retardation (IUGR) (Table II) but the absolute number, although lower in IUGR children, did not reach statistical difference from control values (accent mine). Lymphocyte proliferation in vitro was less than in age-matched controls but was comparable to that in healthy adults. No explanation is offered for this surprising finding. No data are provided to substantiate the lack "of a trend toward expected age-related skin reactivity, lymphocyte numbers, or proliferative responses with increasing age:" The similarity of lymphocyte proliferative capacity in children with IUGR and adults could in fact point to an accelerated maturation in the affected children. A more valid reason for these surprising results may lie in the very small number of children assessed and the very wide scatter of their chronologic ages, making statistical analysis of mean values less reliable. Moreover, all the eight IUGR children had had catch-up growth, indicated by height and weight atSove the tenth percentile at the time of immunologic assessment; this may well indicate a skewed type of sample since a large proportion of IUGR neonates fail to achieve normal physical growth during early childhood. 6 Finally, our original study ~ on fetal malnutrition and postnatal immunocompetence included 26 infants, not 15 as cited. Ferguson did not cite our published data on a much larger
15 8
Editorial correspondence
study sample of 50 IUGR children studied up to 5 years of age.~, a. ~ We had observed that prolonged impairment of immunocompetence is seen mainly in those infants with IUGR who fail to undergo rapid catch-up growth in early childhood and continue to be retarded in physical size. Manerikar ~ has shown reduced number of T cells, impaired lymphocyte proliferation, and failure to achieve tuberculin conversion following neonatal administration of BCG vaccine. Study of paired maternal-fetal sera showed reduced level of IgG antibodies in IUGR infants2 This may further compromise host defenses of affected children. Phagocyte and complement activity are also reduced.'" The relationship between alpha fetoprotein (AFP) and lymphocyte proliferation in vitro is mentioned. This is also observed in vivo. 11 Recent observations 1-~-la suggest that the immunosuppressive property of AFP is critically dependent upon its ability to bind estrogens and perhaps other substances. Dialysis to remove estradiol eliminates the suppressive activity of AFP. R. K. Chandra, M.D., F.R.C.P.(C) Memorial University of Newfoundland Dr. Charles A. Janeway Child Health Centre St. John's, Newfoundland A1A 1R8 Canada REFERENCES
1. Ferguson AC: Prolonged impairment of cellular immunity in children with intrauterine growth retardation, J PEDIATR 93:52, 1978. 2. Chandra RK, Ali SK, Kutty KM, and Chandra S: Thymus-dependent lymphocytes and delayed hypersensitivity in low birth weight infants, Biol Neonate 31:15, 1977. 3. Chandra RK: Immunological consequences of malnutrition including fetal growth retardation, in Hambreaus L, Hanson LA, McFarlane H, editors: Food and immunology, Stockholm, 1977, Almqvist and Wiksell F0rlag, p 58. 4. Manerikar S: Immune status and BCG vaccination in newborns with intrauterine growth retardation, Clin Exp Immunol 26:173, 1976. 5. Moscatelli P, Bricarelli Dagna F, Piccinini A, Tomatis C, and Dufour A: Defective immunocompetence in foetal undernutrition, Helv Paediatr Acta 31:241, 1976. 6. Aetiology, social implications and preventation of low birth weight infants, W H O / M C H / L B W Document, 1978. 7. Chandra RK: Fetal malnutrition and postnatal immunocompetence, Am J Dis Child 129:450, 1975. 8. Chandra RK: Cell-mediated immunity in fetally and postnatally malnourished children from India and Newfoundland, in Suskind RM, editor: Malnutrition and the immune response, New York, 1977, Raven Press, p 111. 9. Chandra RK: Levels of IgG subclasses, tgG, lgM and tetanus antitoxin in paired maternal and foetal sera. Findings in healthy pregnancy and placental insufficiency, in Hemmings WA, editor: Materno-foetal transmission of immunoglobulins. London, 1975, Cambridge University Press, pp. 77-90. 10. Chandra RK: Ontogenetic development of the immune system and effects of fetal growth retardation, J Perinat Med (in press). 11. Chandra RK, and Bhujwala, RA: Elevated alpha-fetopro-
The Journal of Pediatrics July 1979
tein and impaired immuno response in malnutrition, Int Arch Allergy AppI Immunol 53:180, 1977. 12. Fishman WH, and Sell S, editors: Onco-developmental gene expression, New York, 1976, Academic Press, Inc., pp 329-337. 13. Chandra RK: Functional significance of alphafetoprotein during pregnancy. Immunosuppression, estrogen binding and morphogenesis, in Hemmings WA, editor: The Transmission of Proteins Across Living Membranes. Amsterdam, 1979, Elsevier/North Holland.
Refly To the Editor: The omission of Dr. Chandra's paper 1 is regretted. In studies of children with intrauterine growth retardation (IUGR), it is important to define the criteria used in making this diagnosis to exclude those with low birth weight secondary to prematurity, and to define its etiology. The origins of IUGR are numerous and heterogeneous in nature. The effect of these factors on the developing immune system is unlikely to be uniform, and we therefore were careful to specify the origin of IUGR in our population. Moreover, our selection criteria were more stringent than those of other studies >~ in that all of our children weighed less than the 3rd percentile of weight for gestational age rather than the tenth percentile. Chandra contends that catch-up growth is associated with a return of normal immunologic function, but the severity of growth retardation present in the subgroup of his study population I who had catch-up-growth is unclear, an important point since those between the third and tenth percentiles would be expected to be least ~tffected immunologically. Catch-up growth is common and is greatest in those with the lowest weight/length ratio. ~. a Indeed, failure to have an accelerated weight gain in the postnatal period suggests feeding or psychosocial problems leading to inadequate nutrition? which has also been associated with cellular immunodeficiency. ~ It is likely, therefore, that our study population represents a common subgroup of children with IUGR (i.e., secondary to maternal hypertension and placental insufficiency) whose postnatal develop follows the expected pattern. The apparent disparity between the reduced percentage but normal number of rosette forming lymphocytes which we reported underlines the need to record absolute numbers of cells, since decreased percentages of T cells may occur secondarily to increased numbers of B or null cells? The disparity between "normal" T lymphocyte count and diminished lymphocyte proliferation is not unexpected; the former is simply a numerical assessment of ceils which have sheep erythrocyte membranereceptors, whereas the latter requires a complex active response by a subpopulation of lymphocytes stimulated with phytohemagglutinin (PHA). Of great importance in the observation of decreased lymphocyte response is the use of age-related control values. Little is known about lymphocyte proliferation with PHA in healthy children compared to adults. Lymphocytes from newborn infants are known to be substantially more reactive, however, ~-1' and decreased reactivity is likely to be a function of increasing age.
3.
Editorial correspondence
Glaser B, and Smith JL: Leukaemic glaucoma, Br Ophthalmol 50:92, 1966.
Cutis marmorata telangiectatica congenita and neonatal ascites To the Editor: It was with great interest and appreciation that we read the article by South and Jacobs 1 recently published in Tr~E JOURNAL. However, none of the patients reported had any evidence of neonatal liver disease.
15 7
its presence in a patient with CMTC is curious enough that it should be added to the list of possible associated abnormalities. Robert B. Schuhz, M.D. 3939 Hollywood Bird, Hollywood, FL 33021 Samuel Kocos)~is, M.D. Yale University School of Medicine 333 Cedar St. New Haven, CT 06510 REFERENCE
1.
South DA: Cutis marmorata telangiectatica congenita, J PrD1ATR 93:944, 1978.
CASE REPORT
A female infant, born at our institution with neonatal ascites, cutis marmorata telangiectatica congenita (CMTC), and subcutaneous atrophy, was subsequently evaluated at Yale-New Haven Medical Center, Just prior tO delivery of this infant a pelvic sonogram was performed on the mother in anticipation o f possible cephalopelvic disproportion. The sonogram demonstrated a large mass at the level of t h e fetal abdomen. A n intrauterine gastrointestinal series, performed by instillation of sterile barium within the amniotic cavity, revealed normal GI architecture but the presence of ascites. The infant was delivered by cesarean section and the ascites was confirmed. Detailed study both at our institution and at Yale-New Haven Hospital failed to reveal the etiology of the ascites. Histologic examination of cord and placenta was normal. Serum thyroxine was 8.0 /~g/dl. Urine for cytomegalovirus was negative. The serum rubella titer was negative. A urine genetic screen was normal. Liver-spleen scan and bone marrow were normal, The hepatitis B-associated antigen and antibody were negative, and the alpha~-antitrypsin level was 193 mg/dl. Ultrasound disclosed diffuse increase in echoes throughout the liver, consistent with a pathologic hepatocellular process. Liver biopsy revealed mild increase in parenchymal iron but was otherwise normal. The VDRL was negative. Hepatosplenomegaly persisted for the first 4 months of life. SGOT values were elevated' during the first four months of life. A skin biopsy was consistent with CMTC. A computerized tomographic scan o f the head was normal. A barium swallow failed to reveal the presence of esophageal varices. At 3 months Of age quantitative immunoglobulin studies revealed the IgG to be 140 mg/dl and the IgA, 14 mg/dl; IgM was normal. The child is now eight months of age and has persistent CMTC with subcutaneous atrophy over both malar areas. The child has no neurologic deficits and has not experienced any unusual infections. DISCUSSION We have been unable to find any other cases of ascites in association with this syndrome or with other associated syndromes involving hemangiomatous malformations. This finding of ascites and the abnormal hepatic enzymes might suggest that this infant did in fact have an intrauterine infection which is not necessarily organ specific but which has an effect on the vascular system. Perhaps the ascites was purely coincidental, but
Impairment of immunity in children with intrauterine growth retardation To the Editor: The recent report of Ferguson I confirms earlier studies by us ~. and by two other groups ~. ~ demonstrating persistence of impairment of cell-mediated immunity in children with fetal growth retardation. A serious limitation of Ferguson's study is the small size and skewed nature of the sample populations examined. The conclusions on prolonged impairment of cellular immunity are based on observations on only eight children with a wide age range; the exact ages of the eight subjects are not stated. The percentage of rosetting T lymphocytes was significantly reduced in children with intrauterine growth retardation (IUGR) (Table II) but the absolute number, although lower in IUGR children, did not reach statistical difference from control values (accent mine). Lymphocyte proliferation in vitro was less than in age-matched controls but was comparable to that in healthy adults. No explanation is offered for this surprising finding. No data are provided to substantiate the lack "of a trend toward expected age-related skin reactivity, lymphocyte numbers, or proliferative responses with increasing age:" The similarity of lymphocyte proliferative capacity in children with IUGR and adults could in fact point to an accelerated maturation in the affected children. A more valid reason for these surprising results may lie in the very small number of children assessed and the very wide scatter of their chronologic ages, making statistical analysis of mean values less reliable. Moreover, all the eight IUGR children had had catch-up growth, indicated by height and weight atSove the tenth percentile at the time of immunologic assessment; this may well indicate a skewed type of sample since a large proportion of IUGR neonates fail to achieve normal physical growth during early childhood. 6 Finally, our original study ~ on fetal malnutrition and postnatal immunocompetence included 26 infants, not 15 as cited. Ferguson did not cite our published data on a much larger
15 8
Editorial correspondence
study sample of 50 IUGR children studied up to 5 years of age.~, a. ~ We had observed that prolonged impairment of immunocompetence is seen mainly in those infants with IUGR who fail to undergo rapid catch-up growth in early childhood and continue to be retarded in physical size. Manerikar ~ has shown reduced number of T cells, impaired lymphocyte proliferation, and failure to achieve tuberculin conversion following neonatal administration of BCG vaccine. Study of paired maternal-fetal sera showed reduced level of IgG antibodies in IUGR infants2 This may further compromise host defenses of affected children. Phagocyte and complement activity are also reduced.'" The relationship between alpha fetoprotein (AFP) and lymphocyte proliferation in vitro is mentioned. This is also observed in vivo. 11 Recent observations 1-~-la suggest that the immunosuppressive property of AFP is critically dependent upon its ability to bind estrogens and perhaps other substances. Dialysis to remove estradiol eliminates the suppressive activity of AFP. R. K. Chandra, M.D., F.R.C.P.(C) Memorial University of Newfoundland Dr. Charles A. Janeway Child Health Centre St. John's, Newfoundland A1A 1R8 Canada REFERENCES
1. Ferguson AC: Prolonged impairment of cellular immunity in children with intrauterine growth retardation, J PEDIATR 93:52, 1978. 2. Chandra RK, Ali SK, Kutty KM, and Chandra S: Thymus-dependent lymphocytes and delayed hypersensitivity in low birth weight infants, Biol Neonate 31:15, 1977. 3. Chandra RK: Immunological consequences of malnutrition including fetal growth retardation, in Hambreaus L, Hanson LA, McFarlane H, editors: Food and immunology, Stockholm, 1977, Almqvist and Wiksell F0rlag, p 58. 4. Manerikar S: Immune status and BCG vaccination in newborns with intrauterine growth retardation, Clin Exp Immunol 26:173, 1976. 5. Moscatelli P, Bricarelli Dagna F, Piccinini A, Tomatis C, and Dufour A: Defective immunocompetence in foetal undernutrition, Helv Paediatr Acta 31:241, 1976. 6. Aetiology, social implications and preventation of low birth weight infants, W H O / M C H / L B W Document, 1978. 7. Chandra RK: Fetal malnutrition and postnatal immunocompetence, Am J Dis Child 129:450, 1975. 8. Chandra RK: Cell-mediated immunity in fetally and postnatally malnourished children from India and Newfoundland, in Suskind RM, editor: Malnutrition and the immune response, New York, 1977, Raven Press, p 111. 9. Chandra RK: Levels of IgG subclasses, tgG, lgM and tetanus antitoxin in paired maternal and foetal sera. Findings in healthy pregnancy and placental insufficiency, in Hemmings WA, editor: Materno-foetal transmission of immunoglobulins. London, 1975, Cambridge University Press, pp. 77-90. 10. Chandra RK: Ontogenetic development of the immune system and effects of fetal growth retardation, J Perinat Med (in press). 11. Chandra RK, and Bhujwala, RA: Elevated alpha-fetopro-
The Journal of Pediatrics July 1979
tein and impaired immuno response in malnutrition, Int Arch Allergy AppI Immunol 53:180, 1977. 12. Fishman WH, and Sell S, editors: Onco-developmental gene expression, New York, 1976, Academic Press, Inc., pp 329-337. 13. Chandra RK: Functional significance of alphafetoprotein during pregnancy. Immunosuppression, estrogen binding and morphogenesis, in Hemmings WA, editor: The Transmission of Proteins Across Living Membranes. Amsterdam, 1979, Elsevier/North Holland.
Refly To the Editor: The omission of Dr. Chandra's paper 1 is regretted. In studies of children with intrauterine growth retardation (IUGR), it is important to define the criteria used in making this diagnosis to exclude those with low birth weight secondary to prematurity, and to define its etiology. The origins of IUGR are numerous and heterogeneous in nature. The effect of these factors on the developing immune system is unlikely to be uniform, and we therefore were careful to specify the origin of IUGR in our population. Moreover, our selection criteria were more stringent than those of other studies >~ in that all of our children weighed less than the 3rd percentile of weight for gestational age rather than the tenth percentile. Chandra contends that catch-up growth is associated with a return of normal immunologic function, but the severity of growth retardation present in the subgroup of his study population I who had catch-up-growth is unclear, an important point since those between the third and tenth percentiles would be expected to be least ~tffected immunologically. Catch-up growth is common and is greatest in those with the lowest weight/length ratio. ~. a Indeed, failure to have an accelerated weight gain in the postnatal period suggests feeding or psychosocial problems leading to inadequate nutrition? which has also been associated with cellular immunodeficiency. ~ It is likely, therefore, that our study population represents a common subgroup of children with IUGR (i.e., secondary to maternal hypertension and placental insufficiency) whose postnatal develop follows the expected pattern. The apparent disparity between the reduced percentage but normal number of rosette forming lymphocytes which we reported underlines the need to record absolute numbers of cells, since decreased percentages of T cells may occur secondarily to increased numbers of B or null cells? The disparity between "normal" T lymphocyte count and diminished lymphocyte proliferation is not unexpected; the former is simply a numerical assessment of ceils which have sheep erythrocyte membranereceptors, whereas the latter requires a complex active response by a subpopulation of lymphocytes stimulated with phytohemagglutinin (PHA). Of great importance in the observation of decreased lymphocyte response is the use of age-related control values. Little is known about lymphocyte proliferation with PHA in healthy children compared to adults. Lymphocytes from newborn infants are known to be substantially more reactive, however, ~-1' and decreased reactivity is likely to be a function of increasing age.
