842
GROWTH-HORMONE DEFICIENCY IN CONGENITAL RUBELLA M. A. PREECE P. J. KEARNEY W. C. MARSHALL
Departments of Growth and Development and Microbiology, Institute of Child Health, University of London, and Royal Hospital for Sick Children, Bristol
boys with congenital rubella and concomitant growth-hormone deficiency responded to human-growth-hormone replacement and have already (over a period of 18 mo) achieved a significant increase in height. The association of these two diagnoses requires recognition so that treatable endocrine disorders, which are becoming recognised more often in congenital rubella, are always positively excluded when affected children with inexplicable short
Summary
Two
stature are seen.
Introduction
growth retardation is common in conrubella,1,2 although children affected in utero but genital without signs of damage at birth are usually of normal birth-weight.33 Postnatal growth retardation also occurs.4,5 Michaels and Kenny6 reported longitudinal growth studies for 15-33 mo in sixteen infants with congenital rubella. They described three growth patterns. Nine children remained small but grew at normal speed, five showed catch-up growth, and the remaining two showed a progressive deceleration in growth-rate. Investigations of thyroid, adrenal, and pituitary function in INTRAUTERINE
these children revealed no abnormalities. It has generally been held that growth retardation in congenital rubella is not due to a disturbance of endocrine function but rather to the direct effect of the virus on the rate of cell division. We now describe two patients in whom growth-hormone deficiency has been associated with congenital rubella. The response of both children to treatment with exogenous growth hormone for 18 mo is also described.
E. L., Bross, V., Hirayama, T. Cancer, 1960, 13, 559. Carroll, K. K., Khor, H. T. in Progress in Biochemical Pharmacology, Lipids and Tumors (edited by K. K. Carroll); p. 308. New York, 1975. 3. MacMahon, B. J. natn. Cancer Inst. 1973, 50, 21. 4. Dickinson, L. E., MacMahon, B., Cole, P., Brown, J. B. New Engl. J. Med. 1974, 219, 1211. 5. Hill, P., Wynder, E. L., Kumar, H., Helman, P., Rona, R., Kuno, K. Cancer Res. 1976, 35, 4102. 6. Petrakis, N. L. 1st Breast Cancer Task Force Working Conference, National Cancer Institute, Williamsburg, Virginia, February, 1973. 7. Petrakis, N. L., Mason, L., Lee, R., Sugimoto, B., Pawson, S., Catchpool, F. J. natn. Cancer Inst. 1975, 54, 829. 8. Pearson, O. H. in Current Research in Oncology (edited by C. B. Anfinson, M. Potter, and A. N. Schechter); p. 125, New York, 1972. 9. Nagai, N., Longcope, C. Steroids, 1971, 1, 631. 10. Alberts, R. W., Lowry, O. H. Analyt. Chem. 1955, 27, 1829. 11. Potter, J. M., Nestel, P. F. Am. J. clin. Nutr. 1976, 29, 54. 12. Petrakis, N. L., Mason, M. L., Doherty, M., Dupuy, M. D., Sadee, G., Wilson, C. S. Fedn Proc. 1977, 37, abstr. 4714. 13. Chan, P., Didato, F., Cohen, L. Proc. Soc. exp. Biol. Med. 1975, 149, 133. 14. Chan, P., Head, J. F., Cohen, L. A., Wynder, E. L. J. natn. Cancer Inst. (in the press). 15. Hill, P., Wynder, E. L. Lancet, 1976, ii, 806. 16. Wellings, S. R., Jensen, H. M., Marcum, R. G. J. natn. Cancer Inst. 1975, 55, 231. 17. Meites, J., Lu, K. H., Wuttke, W., Welsch, C. W., Nagasawa, H., Quadri, S. K. Rec. Prog. Hormone Res. 1973, 28, 471. 18. Welsch, E. W., Nagasawa, H. Cancer Res. 1977, 37, 951. 19. Robyn, C. Path. Biol., Paris, 1973, 23, 783. 1. 2.
Wynder,
Methods All the physical measurements quoted were carried out in the growth-disorder clinic of the Hospital for Sick Children, Great Ormond Street, by methods previously described.’ The biochemical investigations were done at the Royal Hospital for Sick Children, Bristol, in the first case and at the Hospital for Sick Children, Great Ormond Street, in the second. Serumgrowth-hormone was measured during an insulin-tolerance test and was assayed by radioimmunoassay (1st i.R.p. as standard). Serum-thyroxine and serum-cortisol were measured bv competitiye-protein-binding assay. In the second case, the insu lin-tolerance test was combined with an injection of thyrotrophin-releasing hormone (T.R.H.), 200 jig, and luteinising-hormone-releasing hormone (L.H.R.H.), 100 µg. Thyrotrophin (T.S.H.), luteinising hormone (L.H.), and follicle-stimulating hormone (F.S.H.) were assayed by radioimmunoassay against their respective 1st I.R.P. standards.
Case-reports Case1 This boy was born after a normal term third pregnancy. The mother had no illness or history of contact with rubella during the pregnancy. Birth-weight was 2.9 kg. At age 8 mo he presented to hospital with failure to thrive. Feeding was poor, but there were no other specific symptoms. Sensorineural deafness was detected, and fundal examination revealed typical changes of rubella retinopathy. A rubella hsemagglutination-inhibiting (H.I.) antibody titre of 1/16 000 was demonstrated in his serum. As he was already considerably below the 3rd centile for height and was continuing to grow at a subnormal rate, he was further investigated at age 3 yr. On that occasion an inadequate growth-hormone response to insulin hypoglycaemia was demonstrated, but no other endocrine abnormalities were present. These investigations were repeated 3 yr later when, once again, growth-hormone production was abnormal, with a peak of 1.mi.u./l. He was first seen in the growth-disorder clinic at the Hospital for Sick Children, Great Ormond Street, when he was 6.16 yr of age, at which time his height was 6.6 standard deviations below the mean. He had all the clinical features of growth-hormone deficiency, with high skinfold thickness (reflecting an excess of subcutaneous fat) and hypoplastic genitalia, previously described in association with growth-hormone deficiency.s He had bilateral sensorineural deafness and the retinal changes of congenital rubella. Over the subsequent months his growth was assessed at 3-monthly intervals (see figure), and his stature velocity was 3.4 cm/yr—2.8 standard deviations below the mean for his age. At 705 yr he was started on human-growth-hormone replacement at a dose of 5 LU. three times weekly, and over the next 12 mo his growth velocity increased to 146 cm/yr, which is 11.0standard deviations above the mean for his age. During the same period his subcutaneous fat, as indicated by skinfold thickness at the triceps and subscapular sites, fell from a mean of +07 to -09 standarddeviation units. This is a typical response in severe growthhormone deficiency. After 18 mo treatment his stature (104.1 cm) is 4.3 standard deviations below the mean. Case 2 This boy was born after a 37 wk, but otherwise uneventful second pregnancy. Birth-weight was 2-66 kg. There was no history of rubella or contact with rubella in pregnancy. At age 21 mo he was admitted to the Hospital for Sick Children. Great Ormond Street, for investigation of mental retardation. At this time he was found to have bilateral sensorineural deafness and a mild hypochromic anaemia. At 6 yr he was reported to have the retinal pigmentation typical of congenital rubella. but there were no other clinical features of this condition. apart from severe bilateral deafness. Serological tests revealed
843 have
no
way of assessing whether
adotrophin deficiency, either
T.s.H.
or
His response
deficiency. was striking.
curves of the two patients, compared with normal growth curves for boys. Stippled areas indicate duration of growth-hormone therapy.
Growth
rubella H.i. antibody in a titre of 1/64. He was below the 3rd centile for height (see figure). At 12 yr his mother sought advice because of failure to grow. Examination of previous records revealed a low growth velocity, and he was found to have a normal serum-thyroxine but a poor growth-hormone response to ’Bovril’ (peak value 1.7 mI.u./l). He was first seen in the growth-disorder clinic in January, 1975, at age 12.53 yr, when he was observed to be 3.9 standard deviations below the mean for height, with normal skinfold thickness but a delayed bone age of 8-37 yr. Over the next 12 mo his growth velocity was very low (3-3cm/yr), and repeat investigations showed partial growth-hormone deficiency, with a peak serum-growth-hormone of 10.4 mi.u./l, 90 min after insulin (0.1 1. u.Ag). Serum-thyroxine was 92 µg/dl, but the T.R.H. test was abnormal, with a peak serum-T.s.H. of 5.6 mr.u./l at the start of the test. L.H. and F.S.H. production after L.H.R.H. injection was normal. At 13-52 yr he was started on human-growth-hormone replacement, and over the following 12 mo his growth velocity rose to 6.9cm/yr-a significant increase. During this year he also showed signs of entry into puberty, with testes reaching 6 ml volume by the end of the first year of treatment. After a further 6 mo of treatment, his stature was 137.8 cm.
Discussion These two children, who showed clinical and serological evidence consistent with congenital rubella, present rather different pictures of growth. The first patient presented at an early age with severe growth failure and clinical features that would have been typical of isolated growth-hormone deficiency with or without the features of congenital rubella. When first seen in the growth-disorder clinic he had the excessive subcutaneous fat, extreme short stature, and hypoplastic genitalia suggestive of growth-hormone deficiency. At his present age we
or not
but there
was
he has any gonno evidence of
adrenocorticotrophic-hormone growth-hormone replacement
to
In contrast, the second patient is much less typical, in that his growth failure took rather longer to manifest itself. Although his height was below the 3rd centile as early as age 4 yr, his growth velocity during the next 2-3 yr was normal. This would accord well with some of the patients previously described.6 Subsequently, his growth velocity fell to subnormal levels, and by the time he was seen in the growth-disorder clinic it was obviously abnormal. Even so, he did not show the physical appearance of growth-hormone deficiency. In particular, subcutaneous fat was not excessive, with a mean standard-deviation score of +0-2 when he was first seen. His response to growth-hormone therapy, although significant, has not been as great as in the first patient, probably for a combination of reasons. Firstly, he was started on treatment at a much later- age, and it has previously been shown that earlier treatment with growth hormone yields more satisfactory results.9 Secondly, with a peak concentration of human growth hormone of 10 mI.u./1 in the insulin-tolerance test and his relatively normal growth velocity in the earlier years, it is likely that he was only partially growth-hormone deficient. With his abnormal T.R.H. test it it likely that there is also further hypothalamic damage which may still be progressing, although, as yet, he is clinically euthyroid and has a normal serum-thyroxine. His pituitary gonadotrophin secreting power seemed to be normal, as shown by the normal L.H.R.H. test and by his entry into puberty during his treatment year. The increase in growth velocity after starting growth hormone is very unlikely to be related to the start of puberty, since the onset of the adolescent growth spurt would not be expected to occur at this very early stage of adolescence.10 Similarities between the two cases are also striking. In both cases deafness and retinopathy were the only clinical manifestations of congenital rubella apart from the short stature. Both patients had positive rubella H.I. antibody tests, although in the second case this is harder to interpret, because he was not tested until an age when postnatal infection may have occurred." However, the clinical features of the deafness and characteristic retinopathy are highly suggestive of intrauterine rubella
infection. As Comas and Botancesl2 have stated, there is developing evidence of associated endocrinopathies in congenital rubella, and now we must include growth-hormone deficiency together with diabetes mellitus,13 thyroiditis,14 and hypothyroidism.12 Growth-hormone deficiency is presumably part of a hypothalamic disorder arising, as in our first case, in intrauterine or very early postnatal life or as a more chronic progressive hypothalamic disorder, as shown by the second case reported here. This is consistent with other manifestations of con-
genital rubella, such as deafness, pneumonitis, and skin rashes, which comprise a spectrum of disease which has been termed "late-onset" disease.15 Clinicians should be aware that short stature in patients with congenital rubella may, in some instances (albeit rarely), be due to growth-hormone deficiency which, in itself, is treatable and should therefore be diagnosed as soon as possible.
844 This form of short stature is best diagnosed by observation of a low growth velocity and abnormal growth-hormone secretion on appropriate biochemical testing. For best results from replacement therapy these investigations should be carried out as early as possible. We should like to thank Prof. J: A. Dudgeon and Prof. J. M. Tanner for their helpful comments. W. C. M. is a Wellcome research fellow in the department of microbiology, Institute of Child Health.
Requests for reprints should be addressed to M.A.P., Department of Growth and Development, Institute of Child Health, 30 Guilford Street, London WC1N 1EH. REFERENCES 1. 2.
Gregg, N.
M. Trans.
ophthal.
Soc. Aust.
1941, 3, 35.
Heggie, A. Pediat. Clins. N. Am. 1966, 13, 251. 3. Lejarraga, H., Peckham, C. S. Archs Dis. Childh. 1974, 49, 50.
4.
Swan, C., Tostevin, A. L., Moore, B., Mayo, H., Black, G. H. B. Med. J. Aust. 1943, ii, 201. 5. Plotkin, S. A., Cockran, W., Lindquist, J. M., Cockran, G. G., Schaffer, D. B., Scheie, H. G., Furukawa, T. J. Am. med. Ass. 1967, 200, 435. 6. Michaels, R. H., Kenny, F. M. Pediatrics, Springfield, 1969, 43, 251. 7. Naeye, R. L., Blanc, W. J. Am. med. Ass. 1965, 194, 1277. 8. Tanner, J. M., Whitehouse, R. H., Hughes, P. C. R., Vince, F. P. Archs Dis. Childh. 1971, 46, 745. 9. Preece, M. A., Tanner, J. M. Convegno Internazionale di Endocrinologica Pediatrica, Bologna, 1975. 10. Marshall, W. A., Tanner, J. M. Archs Dis. Childh. 1970, 45, 13. 11. Dudgeon, J. A., Peckham, C. S., Marshall, W. C., Smithells, R. W., Sheppard, S. Hlth Trends, 1973, 5, 75. 12. Comas, A. P., Botances, R. E. J. Pediat. 1976, 88, 1065. 13. Forest, J. M., Menser, M. A., Burgess, J. A. Lancet, 1976, ii, 332. 14. Ziring, P. R., Fedun, B. A., Cooper, L. Z. J. Pediat. 1975, 87, 1002. 15. Marshall, W. C. Intrauterine Infections; p. 3. Ciba Fdn Symp. 10. Amsterdam, 1973.
SPECIFIC CELL-MEDIATED IMMUNE DEFECT IN ACTIVE CYTOMEGALOVIRUS INFECTION OF YOUNG CHILDREN AND THEIR MOTHERS RICHARD C. GEHRZ SUSAN O. KNORR HENRY H.
STEPHEN C. MARKER JANAL M. KALIS
BALFOUR, JR
Department of Pediatrics and Department of Laboratory Medicine and Pathology,
University of Minnesota, Minneapolis, Minnesota, U.S.A.
4 young children with active cytomegalovirus (C.M.V.) infection were found, by an in-vitro lymphocyte-proliferation assay, to have a C.M.V.-specific cell-mediated immune defect. These children had antibodies to C.M.V. and were actively shedding C.M.V. in the urine when studied. Their general cellular immune responses were intact, with normal numbers of T lymphocytes and normal in-vitro responses to mitogens and at least one antigen. 3 of the 4 mothers studied shortly after delivery had decreased cell-mediated immunity to C.M.V. These findings suggest that an antigen-specific immune defect facilitates transmission of virus from mother to infant and permits persistence of viral replication in the offspring.
Summary
Introduction
CYTOMEGALOVIRUS (C.M.V.) is the most common cause of viral-induced psychomotor retarda-
recognised
tion. Approximately 1% of newborn infants are infected,1-3 and at least 10% of those will have some degree of central-nervous-system dysfunction. 1,4 c.M.v. pro-
spectrum of clinical manifestations in neonates, ranging from asymptomatic viruria to fulminant disease
duces
a
involving lungs, liver, spleen, bone-marrow, and central nervous system. Even infants symptom-free at birth may later become deaf.5Children with congenital c.M.v. continue to manifest clinical and virological evidence of infection for many months or years, despite their ability to develop humoral antibodies to c.M.v.’ This suggests an underlying cell-mediated defect in the host’s immune response to the virus. We therefore developed an in-vitro lymphocyte-proliferation assay to concentrated purified c.M.v. antigen, and we have used this to study specific cell-mediated immunity to c.M.v. in 4 children with active c.M.v. infections and their mothers.
.
Patient 1.-This
Case-reports girl (birth-weight
3268 g) was born at 17-year-old primigravida. At birth she had a generalised petechial rash and hepatosplenomegaly. Hyperbilirubinxmia developed at age 15 h. c.M.v. was isolated from nasopharyngeal cultures shortly after birth. She developed normally, but when last examined, at age 11 months, she had hepatosplenomegaly and excreted 102.5 to 105.0 median tissueterm to a
culture infective doses (T.C.I.D.50) of c.m.v. per 0.1 ml of urine. Patient 2.-This boy (birth-weight 3100 g) was born at term to a 17-year-old primigravida. At 3 days of age he became jaundiced, had a liver palpable 6 cm below the right costal margin, and spleen palpable 8 cm below the left costal margin. Bilirubin was 11 mg/dl; serum-glutamate-oxaloacetate-transaminase (S.G.O.T.) 500 I.U.;1. (normal, 7-26 I.U./l); ornithine carbamoyl transferase 6080 units/I (normal 20-690 units/1), platelet-count 100 000/mm3. c.M.v. was first cultured from the urine at 5 days of age. Hepatosplenomegaly, liver-function abnormalities, and thrombocytopenia persisted. At 1 month he was readmitted because of a right upper-lobe pneumonitis which resolved rapidly. He is now 5 months old and is excreting 103 T.C.LD.so OfC.M.V. per 0.1 ml of urine. Patient 3.-This 4-year-old boy (birth-weight 2554 g) was born after a full-term uncomplicated pregnancy to a 22-yearold primigravida. Hyperbilirubinxmia was observed during the first day of life but resolved within 3 days. In the first 9 months of life he showed severe growth and psychomotor retardation. On physical examination at age 9 months he did not have chorioretinitis or hepatosplenomegaly, but he was hypertonic, with mild spastic diplegia. He had no detectable antibodies to rubella, herpes simplex, or Toxoplasma gondii; his c.M.v. complement-fixing titre was 32. During the next 3 years, he manifested generalised psychomotor retardation with loss of developmental milestones, suggesting progressive central-nervous-system disease. Unfortunately, virus cultures were not done until he was 3 years old, when c.Ht.v. viruria was noted. At age 4 he is still shedding 103.5 T .C.I.D.50 of c.nt.v. per 0.ml of urine. Patient 4.-This boy was born after a normal term pregnancy to a 28-year-old gravida 3. The neonatal period was complicated by an unexplained rise in bilirubin to 15 mg/dl which responded quickly to phototherapy. At age 4 months he was readmitted with right middle-lobe pneumonia, fever, hepatosplenomegaly, and hsemolytic ansmia. His height, weight, and head circumference were normal on admission. Haemoglobin was 4.5 g/dl, peripheral-blood smear showed 30% reticulocytes, platelet-count 478 000/mm3 andS.G.O.T. 104 I.u.A The cerebrospinal fluid was normal. Fever and pneumonia resolved
GROWTH-HORMONE DEFICIENCY IN CONGENITAL RUBELLA M. A. PREECE P. J. KEARNEY W. C. MARSHALL
Departments of Growth and Development and Microbiology, Institute of Child Health, University of London, and Royal Hospital for Sick Children, Bristol
boys with congenital rubella and concomitant growth-hormone deficiency responded to human-growth-hormone replacement and have already (over a period of 18 mo) achieved a significant increase in height. The association of these two diagnoses requires recognition so that treatable endocrine disorders, which are becoming recognised more often in congenital rubella, are always positively excluded when affected children with inexplicable short
Summary
Two
stature are seen.
Introduction
growth retardation is common in conrubella,1,2 although children affected in utero but genital without signs of damage at birth are usually of normal birth-weight.33 Postnatal growth retardation also occurs.4,5 Michaels and Kenny6 reported longitudinal growth studies for 15-33 mo in sixteen infants with congenital rubella. They described three growth patterns. Nine children remained small but grew at normal speed, five showed catch-up growth, and the remaining two showed a progressive deceleration in growth-rate. Investigations of thyroid, adrenal, and pituitary function in INTRAUTERINE
these children revealed no abnormalities. It has generally been held that growth retardation in congenital rubella is not due to a disturbance of endocrine function but rather to the direct effect of the virus on the rate of cell division. We now describe two patients in whom growth-hormone deficiency has been associated with congenital rubella. The response of both children to treatment with exogenous growth hormone for 18 mo is also described.
E. L., Bross, V., Hirayama, T. Cancer, 1960, 13, 559. Carroll, K. K., Khor, H. T. in Progress in Biochemical Pharmacology, Lipids and Tumors (edited by K. K. Carroll); p. 308. New York, 1975. 3. MacMahon, B. J. natn. Cancer Inst. 1973, 50, 21. 4. Dickinson, L. E., MacMahon, B., Cole, P., Brown, J. B. New Engl. J. Med. 1974, 219, 1211. 5. Hill, P., Wynder, E. L., Kumar, H., Helman, P., Rona, R., Kuno, K. Cancer Res. 1976, 35, 4102. 6. Petrakis, N. L. 1st Breast Cancer Task Force Working Conference, National Cancer Institute, Williamsburg, Virginia, February, 1973. 7. Petrakis, N. L., Mason, L., Lee, R., Sugimoto, B., Pawson, S., Catchpool, F. J. natn. Cancer Inst. 1975, 54, 829. 8. Pearson, O. H. in Current Research in Oncology (edited by C. B. Anfinson, M. Potter, and A. N. Schechter); p. 125, New York, 1972. 9. Nagai, N., Longcope, C. Steroids, 1971, 1, 631. 10. Alberts, R. W., Lowry, O. H. Analyt. Chem. 1955, 27, 1829. 11. Potter, J. M., Nestel, P. F. Am. J. clin. Nutr. 1976, 29, 54. 12. Petrakis, N. L., Mason, M. L., Doherty, M., Dupuy, M. D., Sadee, G., Wilson, C. S. Fedn Proc. 1977, 37, abstr. 4714. 13. Chan, P., Didato, F., Cohen, L. Proc. Soc. exp. Biol. Med. 1975, 149, 133. 14. Chan, P., Head, J. F., Cohen, L. A., Wynder, E. L. J. natn. Cancer Inst. (in the press). 15. Hill, P., Wynder, E. L. Lancet, 1976, ii, 806. 16. Wellings, S. R., Jensen, H. M., Marcum, R. G. J. natn. Cancer Inst. 1975, 55, 231. 17. Meites, J., Lu, K. H., Wuttke, W., Welsch, C. W., Nagasawa, H., Quadri, S. K. Rec. Prog. Hormone Res. 1973, 28, 471. 18. Welsch, E. W., Nagasawa, H. Cancer Res. 1977, 37, 951. 19. Robyn, C. Path. Biol., Paris, 1973, 23, 783. 1. 2.
Wynder,
Methods All the physical measurements quoted were carried out in the growth-disorder clinic of the Hospital for Sick Children, Great Ormond Street, by methods previously described.’ The biochemical investigations were done at the Royal Hospital for Sick Children, Bristol, in the first case and at the Hospital for Sick Children, Great Ormond Street, in the second. Serumgrowth-hormone was measured during an insulin-tolerance test and was assayed by radioimmunoassay (1st i.R.p. as standard). Serum-thyroxine and serum-cortisol were measured bv competitiye-protein-binding assay. In the second case, the insu lin-tolerance test was combined with an injection of thyrotrophin-releasing hormone (T.R.H.), 200 jig, and luteinising-hormone-releasing hormone (L.H.R.H.), 100 µg. Thyrotrophin (T.S.H.), luteinising hormone (L.H.), and follicle-stimulating hormone (F.S.H.) were assayed by radioimmunoassay against their respective 1st I.R.P. standards.
Case-reports Case1 This boy was born after a normal term third pregnancy. The mother had no illness or history of contact with rubella during the pregnancy. Birth-weight was 2.9 kg. At age 8 mo he presented to hospital with failure to thrive. Feeding was poor, but there were no other specific symptoms. Sensorineural deafness was detected, and fundal examination revealed typical changes of rubella retinopathy. A rubella hsemagglutination-inhibiting (H.I.) antibody titre of 1/16 000 was demonstrated in his serum. As he was already considerably below the 3rd centile for height and was continuing to grow at a subnormal rate, he was further investigated at age 3 yr. On that occasion an inadequate growth-hormone response to insulin hypoglycaemia was demonstrated, but no other endocrine abnormalities were present. These investigations were repeated 3 yr later when, once again, growth-hormone production was abnormal, with a peak of 1.mi.u./l. He was first seen in the growth-disorder clinic at the Hospital for Sick Children, Great Ormond Street, when he was 6.16 yr of age, at which time his height was 6.6 standard deviations below the mean. He had all the clinical features of growth-hormone deficiency, with high skinfold thickness (reflecting an excess of subcutaneous fat) and hypoplastic genitalia, previously described in association with growth-hormone deficiency.s He had bilateral sensorineural deafness and the retinal changes of congenital rubella. Over the subsequent months his growth was assessed at 3-monthly intervals (see figure), and his stature velocity was 3.4 cm/yr—2.8 standard deviations below the mean for his age. At 705 yr he was started on human-growth-hormone replacement at a dose of 5 LU. three times weekly, and over the next 12 mo his growth velocity increased to 146 cm/yr, which is 11.0standard deviations above the mean for his age. During the same period his subcutaneous fat, as indicated by skinfold thickness at the triceps and subscapular sites, fell from a mean of +07 to -09 standarddeviation units. This is a typical response in severe growthhormone deficiency. After 18 mo treatment his stature (104.1 cm) is 4.3 standard deviations below the mean. Case 2 This boy was born after a 37 wk, but otherwise uneventful second pregnancy. Birth-weight was 2-66 kg. There was no history of rubella or contact with rubella in pregnancy. At age 21 mo he was admitted to the Hospital for Sick Children. Great Ormond Street, for investigation of mental retardation. At this time he was found to have bilateral sensorineural deafness and a mild hypochromic anaemia. At 6 yr he was reported to have the retinal pigmentation typical of congenital rubella. but there were no other clinical features of this condition. apart from severe bilateral deafness. Serological tests revealed
843 have
no
way of assessing whether
adotrophin deficiency, either
T.s.H.
or
His response
deficiency. was striking.
curves of the two patients, compared with normal growth curves for boys. Stippled areas indicate duration of growth-hormone therapy.
Growth
rubella H.i. antibody in a titre of 1/64. He was below the 3rd centile for height (see figure). At 12 yr his mother sought advice because of failure to grow. Examination of previous records revealed a low growth velocity, and he was found to have a normal serum-thyroxine but a poor growth-hormone response to ’Bovril’ (peak value 1.7 mI.u./l). He was first seen in the growth-disorder clinic in January, 1975, at age 12.53 yr, when he was observed to be 3.9 standard deviations below the mean for height, with normal skinfold thickness but a delayed bone age of 8-37 yr. Over the next 12 mo his growth velocity was very low (3-3cm/yr), and repeat investigations showed partial growth-hormone deficiency, with a peak serum-growth-hormone of 10.4 mi.u./l, 90 min after insulin (0.1 1. u.Ag). Serum-thyroxine was 92 µg/dl, but the T.R.H. test was abnormal, with a peak serum-T.s.H. of 5.6 mr.u./l at the start of the test. L.H. and F.S.H. production after L.H.R.H. injection was normal. At 13-52 yr he was started on human-growth-hormone replacement, and over the following 12 mo his growth velocity rose to 6.9cm/yr-a significant increase. During this year he also showed signs of entry into puberty, with testes reaching 6 ml volume by the end of the first year of treatment. After a further 6 mo of treatment, his stature was 137.8 cm.
Discussion These two children, who showed clinical and serological evidence consistent with congenital rubella, present rather different pictures of growth. The first patient presented at an early age with severe growth failure and clinical features that would have been typical of isolated growth-hormone deficiency with or without the features of congenital rubella. When first seen in the growth-disorder clinic he had the excessive subcutaneous fat, extreme short stature, and hypoplastic genitalia suggestive of growth-hormone deficiency. At his present age we
or not
but there
was
he has any gonno evidence of
adrenocorticotrophic-hormone growth-hormone replacement
to
In contrast, the second patient is much less typical, in that his growth failure took rather longer to manifest itself. Although his height was below the 3rd centile as early as age 4 yr, his growth velocity during the next 2-3 yr was normal. This would accord well with some of the patients previously described.6 Subsequently, his growth velocity fell to subnormal levels, and by the time he was seen in the growth-disorder clinic it was obviously abnormal. Even so, he did not show the physical appearance of growth-hormone deficiency. In particular, subcutaneous fat was not excessive, with a mean standard-deviation score of +0-2 when he was first seen. His response to growth-hormone therapy, although significant, has not been as great as in the first patient, probably for a combination of reasons. Firstly, he was started on treatment at a much later- age, and it has previously been shown that earlier treatment with growth hormone yields more satisfactory results.9 Secondly, with a peak concentration of human growth hormone of 10 mI.u./1 in the insulin-tolerance test and his relatively normal growth velocity in the earlier years, it is likely that he was only partially growth-hormone deficient. With his abnormal T.R.H. test it it likely that there is also further hypothalamic damage which may still be progressing, although, as yet, he is clinically euthyroid and has a normal serum-thyroxine. His pituitary gonadotrophin secreting power seemed to be normal, as shown by the normal L.H.R.H. test and by his entry into puberty during his treatment year. The increase in growth velocity after starting growth hormone is very unlikely to be related to the start of puberty, since the onset of the adolescent growth spurt would not be expected to occur at this very early stage of adolescence.10 Similarities between the two cases are also striking. In both cases deafness and retinopathy were the only clinical manifestations of congenital rubella apart from the short stature. Both patients had positive rubella H.I. antibody tests, although in the second case this is harder to interpret, because he was not tested until an age when postnatal infection may have occurred." However, the clinical features of the deafness and characteristic retinopathy are highly suggestive of intrauterine rubella
infection. As Comas and Botancesl2 have stated, there is developing evidence of associated endocrinopathies in congenital rubella, and now we must include growth-hormone deficiency together with diabetes mellitus,13 thyroiditis,14 and hypothyroidism.12 Growth-hormone deficiency is presumably part of a hypothalamic disorder arising, as in our first case, in intrauterine or very early postnatal life or as a more chronic progressive hypothalamic disorder, as shown by the second case reported here. This is consistent with other manifestations of con-
genital rubella, such as deafness, pneumonitis, and skin rashes, which comprise a spectrum of disease which has been termed "late-onset" disease.15 Clinicians should be aware that short stature in patients with congenital rubella may, in some instances (albeit rarely), be due to growth-hormone deficiency which, in itself, is treatable and should therefore be diagnosed as soon as possible.
844 This form of short stature is best diagnosed by observation of a low growth velocity and abnormal growth-hormone secretion on appropriate biochemical testing. For best results from replacement therapy these investigations should be carried out as early as possible. We should like to thank Prof. J: A. Dudgeon and Prof. J. M. Tanner for their helpful comments. W. C. M. is a Wellcome research fellow in the department of microbiology, Institute of Child Health.
Requests for reprints should be addressed to M.A.P., Department of Growth and Development, Institute of Child Health, 30 Guilford Street, London WC1N 1EH. REFERENCES 1. 2.
Gregg, N.
M. Trans.
ophthal.
Soc. Aust.
1941, 3, 35.
Heggie, A. Pediat. Clins. N. Am. 1966, 13, 251. 3. Lejarraga, H., Peckham, C. S. Archs Dis. Childh. 1974, 49, 50.
4.
Swan, C., Tostevin, A. L., Moore, B., Mayo, H., Black, G. H. B. Med. J. Aust. 1943, ii, 201. 5. Plotkin, S. A., Cockran, W., Lindquist, J. M., Cockran, G. G., Schaffer, D. B., Scheie, H. G., Furukawa, T. J. Am. med. Ass. 1967, 200, 435. 6. Michaels, R. H., Kenny, F. M. Pediatrics, Springfield, 1969, 43, 251. 7. Naeye, R. L., Blanc, W. J. Am. med. Ass. 1965, 194, 1277. 8. Tanner, J. M., Whitehouse, R. H., Hughes, P. C. R., Vince, F. P. Archs Dis. Childh. 1971, 46, 745. 9. Preece, M. A., Tanner, J. M. Convegno Internazionale di Endocrinologica Pediatrica, Bologna, 1975. 10. Marshall, W. A., Tanner, J. M. Archs Dis. Childh. 1970, 45, 13. 11. Dudgeon, J. A., Peckham, C. S., Marshall, W. C., Smithells, R. W., Sheppard, S. Hlth Trends, 1973, 5, 75. 12. Comas, A. P., Botances, R. E. J. Pediat. 1976, 88, 1065. 13. Forest, J. M., Menser, M. A., Burgess, J. A. Lancet, 1976, ii, 332. 14. Ziring, P. R., Fedun, B. A., Cooper, L. Z. J. Pediat. 1975, 87, 1002. 15. Marshall, W. C. Intrauterine Infections; p. 3. Ciba Fdn Symp. 10. Amsterdam, 1973.
SPECIFIC CELL-MEDIATED IMMUNE DEFECT IN ACTIVE CYTOMEGALOVIRUS INFECTION OF YOUNG CHILDREN AND THEIR MOTHERS RICHARD C. GEHRZ SUSAN O. KNORR HENRY H.
STEPHEN C. MARKER JANAL M. KALIS
BALFOUR, JR
Department of Pediatrics and Department of Laboratory Medicine and Pathology,
University of Minnesota, Minneapolis, Minnesota, U.S.A.
4 young children with active cytomegalovirus (C.M.V.) infection were found, by an in-vitro lymphocyte-proliferation assay, to have a C.M.V.-specific cell-mediated immune defect. These children had antibodies to C.M.V. and were actively shedding C.M.V. in the urine when studied. Their general cellular immune responses were intact, with normal numbers of T lymphocytes and normal in-vitro responses to mitogens and at least one antigen. 3 of the 4 mothers studied shortly after delivery had decreased cell-mediated immunity to C.M.V. These findings suggest that an antigen-specific immune defect facilitates transmission of virus from mother to infant and permits persistence of viral replication in the offspring.
Summary
Introduction
CYTOMEGALOVIRUS (C.M.V.) is the most common cause of viral-induced psychomotor retarda-
recognised
tion. Approximately 1% of newborn infants are infected,1-3 and at least 10% of those will have some degree of central-nervous-system dysfunction. 1,4 c.M.v. pro-
spectrum of clinical manifestations in neonates, ranging from asymptomatic viruria to fulminant disease
duces
a
involving lungs, liver, spleen, bone-marrow, and central nervous system. Even infants symptom-free at birth may later become deaf.5Children with congenital c.M.v. continue to manifest clinical and virological evidence of infection for many months or years, despite their ability to develop humoral antibodies to c.M.v.’ This suggests an underlying cell-mediated defect in the host’s immune response to the virus. We therefore developed an in-vitro lymphocyte-proliferation assay to concentrated purified c.M.v. antigen, and we have used this to study specific cell-mediated immunity to c.M.v. in 4 children with active c.M.v. infections and their mothers.
.
Patient 1.-This
Case-reports girl (birth-weight
3268 g) was born at 17-year-old primigravida. At birth she had a generalised petechial rash and hepatosplenomegaly. Hyperbilirubinxmia developed at age 15 h. c.M.v. was isolated from nasopharyngeal cultures shortly after birth. She developed normally, but when last examined, at age 11 months, she had hepatosplenomegaly and excreted 102.5 to 105.0 median tissueterm to a
culture infective doses (T.C.I.D.50) of c.m.v. per 0.1 ml of urine. Patient 2.-This boy (birth-weight 3100 g) was born at term to a 17-year-old primigravida. At 3 days of age he became jaundiced, had a liver palpable 6 cm below the right costal margin, and spleen palpable 8 cm below the left costal margin. Bilirubin was 11 mg/dl; serum-glutamate-oxaloacetate-transaminase (S.G.O.T.) 500 I.U.;1. (normal, 7-26 I.U./l); ornithine carbamoyl transferase 6080 units/I (normal 20-690 units/1), platelet-count 100 000/mm3. c.M.v. was first cultured from the urine at 5 days of age. Hepatosplenomegaly, liver-function abnormalities, and thrombocytopenia persisted. At 1 month he was readmitted because of a right upper-lobe pneumonitis which resolved rapidly. He is now 5 months old and is excreting 103 T.C.LD.so OfC.M.V. per 0.1 ml of urine. Patient 3.-This 4-year-old boy (birth-weight 2554 g) was born after a full-term uncomplicated pregnancy to a 22-yearold primigravida. Hyperbilirubinxmia was observed during the first day of life but resolved within 3 days. In the first 9 months of life he showed severe growth and psychomotor retardation. On physical examination at age 9 months he did not have chorioretinitis or hepatosplenomegaly, but he was hypertonic, with mild spastic diplegia. He had no detectable antibodies to rubella, herpes simplex, or Toxoplasma gondii; his c.M.v. complement-fixing titre was 32. During the next 3 years, he manifested generalised psychomotor retardation with loss of developmental milestones, suggesting progressive central-nervous-system disease. Unfortunately, virus cultures were not done until he was 3 years old, when c.Ht.v. viruria was noted. At age 4 he is still shedding 103.5 T .C.I.D.50 of c.nt.v. per 0.ml of urine. Patient 4.-This boy was born after a normal term pregnancy to a 28-year-old gravida 3. The neonatal period was complicated by an unexplained rise in bilirubin to 15 mg/dl which responded quickly to phototherapy. At age 4 months he was readmitted with right middle-lobe pneumonia, fever, hepatosplenomegaly, and hsemolytic ansmia. His height, weight, and head circumference were normal on admission. Haemoglobin was 4.5 g/dl, peripheral-blood smear showed 30% reticulocytes, platelet-count 478 000/mm3 andS.G.O.T. 104 I.u.A The cerebrospinal fluid was normal. Fever and pneumonia resolved
