- Email: [email protected]
Congenital concomitants of infantile hypothyroidism
244
Clinical and laboratory observations
patients, we can expect to see increasing numbers of B cell lymphomas in children with H I V infection. The mechanism by which these pediatric lymphoproliferative manifestations are able to develop remains to be elucidated. A better understanding of the pathogenic factors involved will be of importance in designing strategies to prevent or possibly interrupt the development of these disorders. We thank Dr. George Miller, Yale University, for providing the Raji cell line and the EBV-containing recombinant plasmids; Dr. Robert Gallo, National Cancer Institute, for lambda BH-10 clone of HIV; and Dr. Ashok Shende for referring the patient to us.
The Journal of Pediatrics February 1988
6.
7.
8.
9.
REFERENCES
1. Krieg P, Amtmann E, Sauer G. The simultaneous extraction of high molecular-weight DNA and of RNA from solid tumors. Anal Biochem 1983;134:288-94. 2. Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Molec Biol 1975; 98:503-17. 3. Miller G, Gradoville L, Heston L, et al. Structure of the genome of an Epstein-Barr virus derived from saliva of patient with infectious mononucleosis. Cell 1981;24:543-53. 4. Shaw GM, Hahn BH, Arya SK, Groopman JE, Gallo RC, Wong-Staal F. Molecular characterization of human T-cell leukemia (lymphotropic) virus type III in the acquired immunodeficiency syndrome. Science 1984;226:1 t 65-71. 5. Brandsma J, Miller G. Nucleic acid spot hybridization: rapid
10.
11.
12.
13.
quantitative screening of lymphoid cell lines for Epstein-Barr viral DNA. Proc Natl Acad Sci 1980;77:6851-5. Buck BE, Scott GB, Valdes-Dapena M, Parks WP. Kaposi's sarcoma in two infants with acquired immunodeficiency syndrome. J PEDIATR 1983;103:11-3. Gordon EM, Berkowitz R J, Strandjord SE, Kurczynski EM, Goldberg JS, Coccia PF. Burkitt lymphoma in a patient with classic hemophilia receiving factor VIII concentrates. J PEDIATR 1983;103:75-7. Ziegler JL, Beckstead JA, Volberding PA, et al. NonHodgkin's lymphoma in 90 homosexual men: relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. N Engl J Med 1984;311:565-70. Ziegler JL, Anderson M, Klein G, Henle W. Detection of Epstein-Barr virus DNA in American Burkitt's lymphoma. Int J Cancer 1976;17:701-6. Hanto DW, Frizzera G, Gajl-Peczalska K J, Simmons RL. Epstein-Barr virus, Immunodeficiency and B-cell proliferation. Transplantation 1985;39:461-72. Groopman JE, Sullivan JL, Mulder C, et al. Pathogenesis of a B cell lymphoma in a patient with AIDS. Blood 1986;67:6125. Andiman WA, Eastman R, Martin K, et al. Opportunistic lymphoproliferations associated with Epstein-Barr viral DNA in infants and children with AIDS. Lancet 1985;2:1390-3. Birx DL, Redfield RR, Tosato G. Defective regulation of Epstein-Barr virus infection in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related disorders. N Engl J Med 1986;314:874-9.
Congenital concomitants of infantile hypothyroidism New England Congenital Hypothyroidism Collaborative* From the D e p a r t m e n t of Maternal and Child Health, Dartmouth Medical School, Hanover, New Hampshire
Recent reports from Wales and Georgia have described an unusually high incidence of congenital anomalies in infants
Supported by Grant HDl1959 from the National Institutes of Health. Submitted for publication June 30, 1987; accepted Sept. 9, 1987. Reprint requests: Robert Z. Klein, MD, New England Congenital Hypothyroidism Collaborative, Department of Maternal and Child Health, Dartmouth Medical School, Hanover, NH 03756. *Members of the Collaborative: M.B. Arnold, Y. Bapat, Y. Baumgartner, A. Bennet, S.T. Bigos, H.H. Bode, S. Brink, R. Brown, D. Carey, J.D. Crawford, J.E. Crigler, M. Danon, M. Genel, P. Gruppuso, B.L. Haag, J.E. Haddow, S. Hartz, J. Holmes, P.R. Larsen, J. MacCracken, E. Man, M.L. Mitchell, J.M. Orson, L.A. Page, S. Ratzan, H. Reed, E. Reiter, A. Sadeghi-Nejad, B. Senior, W. Tamborlane, S. Waisbren, and R.Z. Klein (coordinator).
with infantile hypothyroidism? ,2 W e therefore reassessed and extended our data on the incidence of congenital concomitant conditions in children with hypothyroidism diagnosed as a result of screening in New England. W e report the results of our study of 297 patients, which coupled with other reports will eventually give the true incidence of congenital concomitants and may even contribute to the understanding of the cause and pathogenesis of sporadic infantile hypothyroidism. METHODS The 297 patients represent two different cohorts. The first consists of 180 patients diagnosed as having permanent hypothyroidism between January 1, 1976, and December 31, 1981. Information regarding congenital anomalies in these patients was obtained in two ways:
Volume 112 Number 2
First, data on congenital anomalies were requested at the time of diagnosis. Second, the attending physicians were asked to fill out questionnaires relevant to congenital concomitants in the winter of 1986. Of the 180 patients, 169 provided adequate information. The second cohort of 169 patients was diagnosed as a result of neonatal screening between January 1, 1982, and August 15, 1986. Information about these infants came solely from a survey conducted in the fall of 1986. Relevant data were obtained for 128 of these patients, it is likely that a few of them will prove to have transient hypothyroidism when they are old enough for it to be safe to withhold treatment for a few weeks. Between January 1, 1976, and August 15, 1986, 1,655,000 newborn infants were screened for hypothyroidism, with an incidence of one patient per 4700 live births. There were three differences between the neonatal reports of congenital anomalies in the first cohort and the results of the survey of the same patients in 1986. One patient diagnosed as having mild pulmonic stenosis in the neonatal period was subsequently found to have an innocent murmur; a patient with suspected subluxation of the hips was finally classified as normal, and a diagnosis of atrial septal defect was established in a patient who had originally been reported as having no anomalies. RESULTS Table I lists the congenital concomitants found in the 297 patients, with the number of patients with each condition in parentheses. As shown in Table II, 2.4% of the children with hypothyroidism had isolated congenital heart disease, and 2% had a trisomic syndrome. This table also notes the differing incidences for the two cohorts of our study population and the incidences in the Welsh and Georgian patients and in an unselected American population. Overall, 7.4% of our patients had a major problem in addition to hypothyroidism, excluding the three patients with late manifesting disease, which would not ordinarily be numbered under the rubric of congenital anomalies, although their conditions presumably were determined before birth. Two patients had euthyroid twins of the same sex: One patient had late manifesting 21-hydroxylase deficiency, and the twin also had late-onset adrenal hyperplasia. The other patient had mild pulmonic stenosis; her twin had no problems. The thyroid deficiency in both patients was due to dyshormonogenesis. Dyshormonogenesis was also diagnosed in a patient with ventricular septal defect and in one with clubfoot. No thyroid was demonstrable on scan in five patients, with Williams syndrome, atrial septal defect, Beal syndrome, glycogen storage disease, and Pierre Robin
Clinical and laboratory observations
245
Table I. Major congenital Concomitants in 297 children with infantile hypothyroidism Cardiac anomalies Pulmonic stenosis (2) Atresia of pulmonary artery (1) Atrial septal defect (2) Isolated ventricular septal defect (1) YSD with coarctation of aorta, overriding pulmonary artery, and patent ductus arteriosus (1) Familial conditions Beal syndrome (contractural arachnodactyly) (1) Microcephaly (1) Conditions associated with intrauterine positional restraint Unilateral clubfoot (1) Bilateral subluxation of hips (2) Miscellaneous Pierre Robin syndrome with ankle clonus, seizures, and death (1) Microcephaly of unknown origin (2) VATER association of anomalies (1) Imperforate anus with rectoperineal fistula and absent left kidney (1) Trisomies Trisomy 21" (5) Trisomy 18 mosaic (1) Late manifesting conditions Williams syndrome, diagnosed at 8 years of age1 (1) Glycogen storage disease, unknown type, diagnosed at 9 months of age (1) Late manifesting 21-hydroxylase deficiencydiagnosed at 4 years of age (1) *OnepatientwithDownsyndromehad an endocardialcushiondefect;three had duodenalatresia. Theseanomaliesnot includedin individuallistings. tHistory of characteristicfacies and mentalretardationat age 2 years.
syndrome, respectively. One patient with a ventricular septal defect had only ectopic thyroid tissue. Finally, four patients with hypothyroidism also had spastic diplegia or quadriplegia. One of these patients was born after 26 weeks of gestation, weighing 700 g; the others were born without problems at full term. Another patient's hypothyroidism may still prove to be transient. DISCUSSION The association of trisomic syndromes and hypothyroidism is well known and occurs most frequently in Down syndrome. In this condition transient hypothyroidism, compensated thyroid disease, idiopathic permanent hypothyroidism, and acquired hypothyroidism following Hashimoto thyroiditis are all common. 3 Fernhoff et al. 2 reported one instance of trisomy 21 among 100 children with hypothyroidism diagnosed as a result of screening, and Banforth et al? reported one patient with trisomy 9 and one with trisomy 21 among the 34 patients with hypothyroidism uncovered by the Welsh screening program. We
246
Clinical and laboratory observations
The Journal of Pediatrics February 1988
T a b l e II. Incidence (%) of major congenital anomalies* (diagnosable in neonatal period) Infants with hypothyroidism
Cardiovascular Cohort 1, 2 Trisomies Cohort 1, 2 Other Cohort 1, 2 Total Cohort 1, 2
Unselected births
New England
Georgia 2
Wales I
United States 6
2.4 (1.8, 3.1) 2.0 (1.2, 3.1) 3.0 (3.0, 3.1) 7.4 (5.9, 9.4)
13
5.9
0.8
1
5.9
0.1
9
8.8
2.1
23
20.6
3.0
Cohort 1 included 169 patients;cohort 2, 128 patients. *Diagnosisin neonatalperiod.
suspect that in these conditions the thyroid disease is part of the syndrome determined by the mechanism causing the other manifestations of the syndrome or is secondary to a pathophysiologic change in the syndrome. The first would be analogous to the minimal or transient hypothyroidism described in pseudohypoparathyroidism,4,5 due to a defect in the guanine nucleotide regulatory protein of adenyl cyclase, causing resistance to thyrotropin as it does to parathormone. The second is analagous to the increased incidence of Hashimoto thyroiditis in children with Down syndrome, thought to be secondary to the immune abnormalities of the syndrome. Similarly, the hypothyroidism in the two brothers reported by Banforth et al., ~ with the syndrome of spiky hair, midfacial anomalies, and hypoplastic larynx and epiglottis, might be considered to be a part of or secondary to the syndrome. In comparing our figures with national figures (3%) for the incidence of congenital anomalies, we eliminated the three patients with conditions manifesting themselves after discharge from the newborn nursery and the patients with cerebral palsy, because the national survey does not include late manifesting conditions or cerebral palsy. 6 The incidence in our series was significantly higher than that in the control population by normal approximation to binomial analysis (P <0.01). The difference is accounted for by the higher incidence of trisomic conditions, which were 20 times as common in our patients with hypothyroidism. The incidence of congenital cardiac anomalies in our cohorts is not statistically significantly higher than reported by the national study (P >0.05). The incidence of late manifesting congenital concomitants in our series is 1%, compared with approximately 2.4% reported by Holmes 7 in 18,000 babies born at the Boston Lying-In Hospital. The cause of the threefold differences in incidence of congenital concomitants in the three reported series is uncertain. It may well result from the small numbers of children observed for relatively uncommon conditions.
This conclusion is suggested by the different incidences (parentheses, Table II) when our patients are divided into two cohorts, both of which are bigger than the series from either Wales or Georgia/,2 Although the first cohort was followed carefully by members of the Collaborative and information was missing for only 11 of 180 patients born with hypothyroidism during the period, the incidence in this cohort was less than that in the second cohort, in which information was obtained only by survey and was totally lacking for 41 of 169 patients with hypothyroidism born during the relevant period. We had no reported cases of isolated persistent patent ductus arteriosus in our patients, but eight patients had this condition among the 134 hypothyroid infants in the other two reports. Should patent ductus arteriosus be listed as a congenital cardiovascular anomaly? It may reflect a postnatal increased secretion of materials such as prostaglandins. The more important question is whether it may be secondary to prenatal thyroid deficiency and thus part of the disease manifestations. Late intrauterine hypothyroidism might prevent maturation of the involved vasculature so that it responds abnormally to postnatal stimuli, or as in the Georgia series, hypothyroidism may be associated with an increased incidence of respiratory distress syndrome, which leads to maintenance of patency of the ductus. What causes a high incidence of congenital abnormalities in infants with hypothyroidism? Inasmuch as thyroxine first appears in the fetal thyroid and serum in miniscule amounts at 11 to 12 weeks gestation, it is unlikely that thyroxine deficiency can be the cause of the accompanying anomalies. The facile explanation that the same teratogenic mechanism that causes the congenital abnormality causes the hypothyroidism breaks down when significant numbers of patients with genetically determined dyshormonogenesis are found among children with both hypothyroidism and another congenital condition. It could be
Volume 112 Number 2
postulated that the recessive genes causing dyshormonogenesis promote teratogenesis. In the Welsh series, three patients with hypothyroidism with congenital concomitants had nondemonstrable thyroid glands on scanning, three were not scanned, and one had a normal scan. The last patient may have had dyshormonogenesis, as could those not scanned. The diagnosis of dyshormonogenesis was not made by the Georgia program. They did perform scans in 42 patients: Eleven had ectopic thyroid tissue, 15 had no demonstrable glands, and 16 had what is described as nonfunctioning normally sited glands. We assume that the scans were made with technetium and that enlargement could not be definitively determined. Hence a distinction between goiter and an incompletely atrophied gland could not be made. Scans were performed in 12 of the patients with concomitant conditions, and five had normally sited nonfunctional thyroid glands. We have previously reported a 22% incidence of dyshormonogenesis in 95 patients with infantile hypothyroidism) Diagnosis was made on the basis of goiters demonstrated by palpation or by thyroid imaging or on the basis of a similarly affected sibling with hypothyroidism. Information enabling us to categorize the type of thyroid problem was available for only 10 of our patients with concomitant congenital conditions: four were diagnosed as having dyshormonogenesis. We do not know the reason for the higher incidence of spastic diplegia or quadriplegia among our patients compared with that found in the study of the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, one per 241. 9 No cases of cerebral palsy were found in the series from Wales (Lazarus J: personal communication) or from Georgia. 2 The possibility of a chance cluster of cases is made more likely by our finding three of the patients in the first cohort and only one patient in the second; this fourth patient might have transient hypothythyroidism. A pooling of many more series is needed to assess the significance of this finding. Certainly, if there is an increased incidence of spastic diplegia or quadriplegia in infants with hypothyroidism, intrauterine thyroid deficiency might create the
Clinical and laboratory observations
247
anlage for its development. This possibility is of special interest because of the well-known occurrence of spastic palsies and other central nervous system abnormalities in endemic cretinism, particularly in those who became euthyroid by birth or shortly thereafter.l~ In support of this speculation is the report of Nelson and Ellenberg9 that prenatal risk factors accounted for 34% of cases of cerebral palsy in the previously mentioned survey and that the addition of perinatal factors in their multivariate analysis accounted for only 3% more. We thank Drs. John M. Graham, Jr., and Lewis B. Holmes for their kind attempts to educate us about teratogenesis. Any misconceptions in this report result from the inadequacies of the students, not of the teachers. REFERENCES
1. Banforth JS, Hughes I, Lazarus J, John R. Congenital anomalic~ associated with hypothyroidism. Arch Dis Child 1986;61:608-9. 2. Fernhoff PM, Brown AL, Elsas LJ. Congenital hypothyroidism: increased risk of neonatai morbidity results in delayed treatment. Lancet 1987;1:490-1. 3. Cutler ET, Benezra-Obeiter R, Brink SJ. Thyroid function in young children with Down syndrome. Am J Dis Child 1986; 140:479-83. 4. Klein RZ. Infantile hypothyroidism then and now: the results of neonatal screening. Curr Probl Pediatr 1985;15:1-58. 5. LevineMA, Downe RW Jr, Moses AM, et al. Resistance to multiple hormones in patients with pseudohypoparathyroidism. Am J Med 1983;74:545-56. 6. Centers for Disease Control: Congenital Malformations Surveillance. Washington, D.C.: U.S. Department of Health and Human Services. 1985:23-5. 7. Holmes LB. Congenital malformations. In: Nelson's textbook of pediatrics, 1lth ed. Philadelphia: WB Saunders, 1979:3701. 8. New England Congenital Hypothyroidism Collaboratove. Characteristics of infantile hypothyroidism discovered on neonatal screening. J Pediatr 1984;104:539-44. 9. Nelson KB, Ellenberg JH. Antecedents of cerebral palsy. N Engl J Med 1986;315:81-8. 10. Koenig MD. Endemic goiter and endemic cretinism. In: Gardner LI, ed. Endocrine and genetic disease in childhood and adolescence, ed 2. Philadelphia: WB Saunders, 1975:2609.
Clinical and laboratory observations
patients, we can expect to see increasing numbers of B cell lymphomas in children with H I V infection. The mechanism by which these pediatric lymphoproliferative manifestations are able to develop remains to be elucidated. A better understanding of the pathogenic factors involved will be of importance in designing strategies to prevent or possibly interrupt the development of these disorders. We thank Dr. George Miller, Yale University, for providing the Raji cell line and the EBV-containing recombinant plasmids; Dr. Robert Gallo, National Cancer Institute, for lambda BH-10 clone of HIV; and Dr. Ashok Shende for referring the patient to us.
The Journal of Pediatrics February 1988
6.
7.
8.
9.
REFERENCES
1. Krieg P, Amtmann E, Sauer G. The simultaneous extraction of high molecular-weight DNA and of RNA from solid tumors. Anal Biochem 1983;134:288-94. 2. Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Molec Biol 1975; 98:503-17. 3. Miller G, Gradoville L, Heston L, et al. Structure of the genome of an Epstein-Barr virus derived from saliva of patient with infectious mononucleosis. Cell 1981;24:543-53. 4. Shaw GM, Hahn BH, Arya SK, Groopman JE, Gallo RC, Wong-Staal F. Molecular characterization of human T-cell leukemia (lymphotropic) virus type III in the acquired immunodeficiency syndrome. Science 1984;226:1 t 65-71. 5. Brandsma J, Miller G. Nucleic acid spot hybridization: rapid
10.
11.
12.
13.
quantitative screening of lymphoid cell lines for Epstein-Barr viral DNA. Proc Natl Acad Sci 1980;77:6851-5. Buck BE, Scott GB, Valdes-Dapena M, Parks WP. Kaposi's sarcoma in two infants with acquired immunodeficiency syndrome. J PEDIATR 1983;103:11-3. Gordon EM, Berkowitz R J, Strandjord SE, Kurczynski EM, Goldberg JS, Coccia PF. Burkitt lymphoma in a patient with classic hemophilia receiving factor VIII concentrates. J PEDIATR 1983;103:75-7. Ziegler JL, Beckstead JA, Volberding PA, et al. NonHodgkin's lymphoma in 90 homosexual men: relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. N Engl J Med 1984;311:565-70. Ziegler JL, Anderson M, Klein G, Henle W. Detection of Epstein-Barr virus DNA in American Burkitt's lymphoma. Int J Cancer 1976;17:701-6. Hanto DW, Frizzera G, Gajl-Peczalska K J, Simmons RL. Epstein-Barr virus, Immunodeficiency and B-cell proliferation. Transplantation 1985;39:461-72. Groopman JE, Sullivan JL, Mulder C, et al. Pathogenesis of a B cell lymphoma in a patient with AIDS. Blood 1986;67:6125. Andiman WA, Eastman R, Martin K, et al. Opportunistic lymphoproliferations associated with Epstein-Barr viral DNA in infants and children with AIDS. Lancet 1985;2:1390-3. Birx DL, Redfield RR, Tosato G. Defective regulation of Epstein-Barr virus infection in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related disorders. N Engl J Med 1986;314:874-9.
Congenital concomitants of infantile hypothyroidism New England Congenital Hypothyroidism Collaborative* From the D e p a r t m e n t of Maternal and Child Health, Dartmouth Medical School, Hanover, New Hampshire
Recent reports from Wales and Georgia have described an unusually high incidence of congenital anomalies in infants
Supported by Grant HDl1959 from the National Institutes of Health. Submitted for publication June 30, 1987; accepted Sept. 9, 1987. Reprint requests: Robert Z. Klein, MD, New England Congenital Hypothyroidism Collaborative, Department of Maternal and Child Health, Dartmouth Medical School, Hanover, NH 03756. *Members of the Collaborative: M.B. Arnold, Y. Bapat, Y. Baumgartner, A. Bennet, S.T. Bigos, H.H. Bode, S. Brink, R. Brown, D. Carey, J.D. Crawford, J.E. Crigler, M. Danon, M. Genel, P. Gruppuso, B.L. Haag, J.E. Haddow, S. Hartz, J. Holmes, P.R. Larsen, J. MacCracken, E. Man, M.L. Mitchell, J.M. Orson, L.A. Page, S. Ratzan, H. Reed, E. Reiter, A. Sadeghi-Nejad, B. Senior, W. Tamborlane, S. Waisbren, and R.Z. Klein (coordinator).
with infantile hypothyroidism? ,2 W e therefore reassessed and extended our data on the incidence of congenital concomitant conditions in children with hypothyroidism diagnosed as a result of screening in New England. W e report the results of our study of 297 patients, which coupled with other reports will eventually give the true incidence of congenital concomitants and may even contribute to the understanding of the cause and pathogenesis of sporadic infantile hypothyroidism. METHODS The 297 patients represent two different cohorts. The first consists of 180 patients diagnosed as having permanent hypothyroidism between January 1, 1976, and December 31, 1981. Information regarding congenital anomalies in these patients was obtained in two ways:
Volume 112 Number 2
First, data on congenital anomalies were requested at the time of diagnosis. Second, the attending physicians were asked to fill out questionnaires relevant to congenital concomitants in the winter of 1986. Of the 180 patients, 169 provided adequate information. The second cohort of 169 patients was diagnosed as a result of neonatal screening between January 1, 1982, and August 15, 1986. Information about these infants came solely from a survey conducted in the fall of 1986. Relevant data were obtained for 128 of these patients, it is likely that a few of them will prove to have transient hypothyroidism when they are old enough for it to be safe to withhold treatment for a few weeks. Between January 1, 1976, and August 15, 1986, 1,655,000 newborn infants were screened for hypothyroidism, with an incidence of one patient per 4700 live births. There were three differences between the neonatal reports of congenital anomalies in the first cohort and the results of the survey of the same patients in 1986. One patient diagnosed as having mild pulmonic stenosis in the neonatal period was subsequently found to have an innocent murmur; a patient with suspected subluxation of the hips was finally classified as normal, and a diagnosis of atrial septal defect was established in a patient who had originally been reported as having no anomalies. RESULTS Table I lists the congenital concomitants found in the 297 patients, with the number of patients with each condition in parentheses. As shown in Table II, 2.4% of the children with hypothyroidism had isolated congenital heart disease, and 2% had a trisomic syndrome. This table also notes the differing incidences for the two cohorts of our study population and the incidences in the Welsh and Georgian patients and in an unselected American population. Overall, 7.4% of our patients had a major problem in addition to hypothyroidism, excluding the three patients with late manifesting disease, which would not ordinarily be numbered under the rubric of congenital anomalies, although their conditions presumably were determined before birth. Two patients had euthyroid twins of the same sex: One patient had late manifesting 21-hydroxylase deficiency, and the twin also had late-onset adrenal hyperplasia. The other patient had mild pulmonic stenosis; her twin had no problems. The thyroid deficiency in both patients was due to dyshormonogenesis. Dyshormonogenesis was also diagnosed in a patient with ventricular septal defect and in one with clubfoot. No thyroid was demonstrable on scan in five patients, with Williams syndrome, atrial septal defect, Beal syndrome, glycogen storage disease, and Pierre Robin
Clinical and laboratory observations
245
Table I. Major congenital Concomitants in 297 children with infantile hypothyroidism Cardiac anomalies Pulmonic stenosis (2) Atresia of pulmonary artery (1) Atrial septal defect (2) Isolated ventricular septal defect (1) YSD with coarctation of aorta, overriding pulmonary artery, and patent ductus arteriosus (1) Familial conditions Beal syndrome (contractural arachnodactyly) (1) Microcephaly (1) Conditions associated with intrauterine positional restraint Unilateral clubfoot (1) Bilateral subluxation of hips (2) Miscellaneous Pierre Robin syndrome with ankle clonus, seizures, and death (1) Microcephaly of unknown origin (2) VATER association of anomalies (1) Imperforate anus with rectoperineal fistula and absent left kidney (1) Trisomies Trisomy 21" (5) Trisomy 18 mosaic (1) Late manifesting conditions Williams syndrome, diagnosed at 8 years of age1 (1) Glycogen storage disease, unknown type, diagnosed at 9 months of age (1) Late manifesting 21-hydroxylase deficiencydiagnosed at 4 years of age (1) *OnepatientwithDownsyndromehad an endocardialcushiondefect;three had duodenalatresia. Theseanomaliesnot includedin individuallistings. tHistory of characteristicfacies and mentalretardationat age 2 years.
syndrome, respectively. One patient with a ventricular septal defect had only ectopic thyroid tissue. Finally, four patients with hypothyroidism also had spastic diplegia or quadriplegia. One of these patients was born after 26 weeks of gestation, weighing 700 g; the others were born without problems at full term. Another patient's hypothyroidism may still prove to be transient. DISCUSSION The association of trisomic syndromes and hypothyroidism is well known and occurs most frequently in Down syndrome. In this condition transient hypothyroidism, compensated thyroid disease, idiopathic permanent hypothyroidism, and acquired hypothyroidism following Hashimoto thyroiditis are all common. 3 Fernhoff et al. 2 reported one instance of trisomy 21 among 100 children with hypothyroidism diagnosed as a result of screening, and Banforth et al? reported one patient with trisomy 9 and one with trisomy 21 among the 34 patients with hypothyroidism uncovered by the Welsh screening program. We
246
Clinical and laboratory observations
The Journal of Pediatrics February 1988
T a b l e II. Incidence (%) of major congenital anomalies* (diagnosable in neonatal period) Infants with hypothyroidism
Cardiovascular Cohort 1, 2 Trisomies Cohort 1, 2 Other Cohort 1, 2 Total Cohort 1, 2
Unselected births
New England
Georgia 2
Wales I
United States 6
2.4 (1.8, 3.1) 2.0 (1.2, 3.1) 3.0 (3.0, 3.1) 7.4 (5.9, 9.4)
13
5.9
0.8
1
5.9
0.1
9
8.8
2.1
23
20.6
3.0
Cohort 1 included 169 patients;cohort 2, 128 patients. *Diagnosisin neonatalperiod.
suspect that in these conditions the thyroid disease is part of the syndrome determined by the mechanism causing the other manifestations of the syndrome or is secondary to a pathophysiologic change in the syndrome. The first would be analogous to the minimal or transient hypothyroidism described in pseudohypoparathyroidism,4,5 due to a defect in the guanine nucleotide regulatory protein of adenyl cyclase, causing resistance to thyrotropin as it does to parathormone. The second is analagous to the increased incidence of Hashimoto thyroiditis in children with Down syndrome, thought to be secondary to the immune abnormalities of the syndrome. Similarly, the hypothyroidism in the two brothers reported by Banforth et al., ~ with the syndrome of spiky hair, midfacial anomalies, and hypoplastic larynx and epiglottis, might be considered to be a part of or secondary to the syndrome. In comparing our figures with national figures (3%) for the incidence of congenital anomalies, we eliminated the three patients with conditions manifesting themselves after discharge from the newborn nursery and the patients with cerebral palsy, because the national survey does not include late manifesting conditions or cerebral palsy. 6 The incidence in our series was significantly higher than that in the control population by normal approximation to binomial analysis (P <0.01). The difference is accounted for by the higher incidence of trisomic conditions, which were 20 times as common in our patients with hypothyroidism. The incidence of congenital cardiac anomalies in our cohorts is not statistically significantly higher than reported by the national study (P >0.05). The incidence of late manifesting congenital concomitants in our series is 1%, compared with approximately 2.4% reported by Holmes 7 in 18,000 babies born at the Boston Lying-In Hospital. The cause of the threefold differences in incidence of congenital concomitants in the three reported series is uncertain. It may well result from the small numbers of children observed for relatively uncommon conditions.
This conclusion is suggested by the different incidences (parentheses, Table II) when our patients are divided into two cohorts, both of which are bigger than the series from either Wales or Georgia/,2 Although the first cohort was followed carefully by members of the Collaborative and information was missing for only 11 of 180 patients born with hypothyroidism during the period, the incidence in this cohort was less than that in the second cohort, in which information was obtained only by survey and was totally lacking for 41 of 169 patients with hypothyroidism born during the relevant period. We had no reported cases of isolated persistent patent ductus arteriosus in our patients, but eight patients had this condition among the 134 hypothyroid infants in the other two reports. Should patent ductus arteriosus be listed as a congenital cardiovascular anomaly? It may reflect a postnatal increased secretion of materials such as prostaglandins. The more important question is whether it may be secondary to prenatal thyroid deficiency and thus part of the disease manifestations. Late intrauterine hypothyroidism might prevent maturation of the involved vasculature so that it responds abnormally to postnatal stimuli, or as in the Georgia series, hypothyroidism may be associated with an increased incidence of respiratory distress syndrome, which leads to maintenance of patency of the ductus. What causes a high incidence of congenital abnormalities in infants with hypothyroidism? Inasmuch as thyroxine first appears in the fetal thyroid and serum in miniscule amounts at 11 to 12 weeks gestation, it is unlikely that thyroxine deficiency can be the cause of the accompanying anomalies. The facile explanation that the same teratogenic mechanism that causes the congenital abnormality causes the hypothyroidism breaks down when significant numbers of patients with genetically determined dyshormonogenesis are found among children with both hypothyroidism and another congenital condition. It could be
Volume 112 Number 2
postulated that the recessive genes causing dyshormonogenesis promote teratogenesis. In the Welsh series, three patients with hypothyroidism with congenital concomitants had nondemonstrable thyroid glands on scanning, three were not scanned, and one had a normal scan. The last patient may have had dyshormonogenesis, as could those not scanned. The diagnosis of dyshormonogenesis was not made by the Georgia program. They did perform scans in 42 patients: Eleven had ectopic thyroid tissue, 15 had no demonstrable glands, and 16 had what is described as nonfunctioning normally sited glands. We assume that the scans were made with technetium and that enlargement could not be definitively determined. Hence a distinction between goiter and an incompletely atrophied gland could not be made. Scans were performed in 12 of the patients with concomitant conditions, and five had normally sited nonfunctional thyroid glands. We have previously reported a 22% incidence of dyshormonogenesis in 95 patients with infantile hypothyroidism) Diagnosis was made on the basis of goiters demonstrated by palpation or by thyroid imaging or on the basis of a similarly affected sibling with hypothyroidism. Information enabling us to categorize the type of thyroid problem was available for only 10 of our patients with concomitant congenital conditions: four were diagnosed as having dyshormonogenesis. We do not know the reason for the higher incidence of spastic diplegia or quadriplegia among our patients compared with that found in the study of the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, one per 241. 9 No cases of cerebral palsy were found in the series from Wales (Lazarus J: personal communication) or from Georgia. 2 The possibility of a chance cluster of cases is made more likely by our finding three of the patients in the first cohort and only one patient in the second; this fourth patient might have transient hypothythyroidism. A pooling of many more series is needed to assess the significance of this finding. Certainly, if there is an increased incidence of spastic diplegia or quadriplegia in infants with hypothyroidism, intrauterine thyroid deficiency might create the
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anlage for its development. This possibility is of special interest because of the well-known occurrence of spastic palsies and other central nervous system abnormalities in endemic cretinism, particularly in those who became euthyroid by birth or shortly thereafter.l~ In support of this speculation is the report of Nelson and Ellenberg9 that prenatal risk factors accounted for 34% of cases of cerebral palsy in the previously mentioned survey and that the addition of perinatal factors in their multivariate analysis accounted for only 3% more. We thank Drs. John M. Graham, Jr., and Lewis B. Holmes for their kind attempts to educate us about teratogenesis. Any misconceptions in this report result from the inadequacies of the students, not of the teachers. REFERENCES
1. Banforth JS, Hughes I, Lazarus J, John R. Congenital anomalic~ associated with hypothyroidism. Arch Dis Child 1986;61:608-9. 2. Fernhoff PM, Brown AL, Elsas LJ. Congenital hypothyroidism: increased risk of neonatai morbidity results in delayed treatment. Lancet 1987;1:490-1. 3. Cutler ET, Benezra-Obeiter R, Brink SJ. Thyroid function in young children with Down syndrome. Am J Dis Child 1986; 140:479-83. 4. Klein RZ. Infantile hypothyroidism then and now: the results of neonatal screening. Curr Probl Pediatr 1985;15:1-58. 5. LevineMA, Downe RW Jr, Moses AM, et al. Resistance to multiple hormones in patients with pseudohypoparathyroidism. Am J Med 1983;74:545-56. 6. Centers for Disease Control: Congenital Malformations Surveillance. Washington, D.C.: U.S. Department of Health and Human Services. 1985:23-5. 7. Holmes LB. Congenital malformations. In: Nelson's textbook of pediatrics, 1lth ed. Philadelphia: WB Saunders, 1979:3701. 8. New England Congenital Hypothyroidism Collaboratove. Characteristics of infantile hypothyroidism discovered on neonatal screening. J Pediatr 1984;104:539-44. 9. Nelson KB, Ellenberg JH. Antecedents of cerebral palsy. N Engl J Med 1986;315:81-8. 10. Koenig MD. Endemic goiter and endemic cretinism. In: Gardner LI, ed. Endocrine and genetic disease in childhood and adolescence, ed 2. Philadelphia: WB Saunders, 1975:2609.