Aust. paediat. J . (1977), 13: 122-124
Autoimmune Thyroiditis in a Case of I8p- Syndrome Feltow, Department
P. D. GLUCKMAN Aucklund, Azcckknd, New Zealand
01 Pediatrics University of
Gluckman, P. D. (1977). Aust. paediat. I., 13, 122-124. Autoimmune thyroiditis in a case of 18p- syndrome. A case of a 16-year-old female with autoimmune thyroiditis and a deletion of the short arm of a chromosome 18 (46, xx, 18p-) is described. Evidence for other autoimmune phenomena was also present. The association between this chromosomal aberration and autoimmune disease is reviewed.
HASHIMOTO’S THYROIDITIS IN A CASE OF 18pDeletion of the short arm of chromosome 18 presents with a varying clinical picture ranging from mild to severe. Two major clinical patterns have emerged from the 64 cases reported in the literature (Lurie and Lazjuk, 1972, Fitzgerald, 1974, Kistenmacher et al., 1973). N‘me cases with arrhinencephaly and associated severe CNS abnormality have been reported. The majority of the other cases have shown a milder form in which the most common features are mental retardation, growth failure; orbital malformation, low set floppy ears, severe dental decay, acromicria and partial webbing of the second and third toes. In addition, many features suggestive of Turner’s Syndrome are reported. These include webbing of the neck and a shieldlike chest. Deficiency of the immunoglobin IgA has been reported in 13 cases as well as in the other abnormalities of the 18 chromosome, 18q- and 18r. Lurie and Lazjuk (1972) report 8 cases of endocrinopathy in a review of 62 cases but details have only been published in 4 cases, 2 being described as hypothyroid, one of whom had thyroiditis. Kistenmacher et al. (1973) describe one additional case with diabetes, autoimmune thyroiditis and possible Sjogren’s syndrome. This report describes a further case of 18p- syndrome with associated autoimmune thyroiditis. CASE REPORT The propositus, a 17-year-old Caucasian female was the product of a pregnancy comReceived November 25, 1976.
plicated by hypertension, delivered following surgical induction at 36 week gestation, and weighed 2,750 gm. At the time of delivery the maternal age was 30 and paternal age 36. Mother’s first pregnancy terminated with a stillbirth with no apparent physical stigmata, and there had been one spontaneous abortion. There were 2 normal younger siblings. The neonatal course was complicated by mild respiratory distress. She appeared to have normal development in the first year of life, but when at 18 months she was admitted to hospital with meningitis it was noted that she was not yet walking on her own. By the age of 5 years psychomotor retardation was obvious and she later attended a special school for intelIectually impaired children. At the age of 16 she was referred for evaluation of a goitre first noticed at the age of 13, in association with symptoms of hypothyroidism. There was no history of joint disease. At that time her height was 140 cm (11 cm below 3rd centile), weight 40 kg (10th centile), head circumference 58.5 cm (40th centile) . She was overtly hypothyroid with a diffusely enlarged firm thyroid weighing about 80 g. Other physical features were a low nuchal hairline, short webbed neck, irregular poor dentition with multiple caries, bilateral ptosis, large floppy ears, and short fingers and toes, particularly the 4th and 5th metacarpals. Her B.P. was 130/90; there was no evidence of aortic coarctation, no cardiomegaly and there was a grade 2/4 ejection systolic murmur at the left sternal edge. Puberty was complete. Skeletal survey demonstrated a thoracolumbar scoliosis, 6 lumbar vertebrae and spina bifida occulta of the 6th vertebra.
123
5
IGROUP A)
(GROUP 6 )
FIGURE 1: Karyotypc of a trypsin G-handed cell from the patient.
LABORATORY STUDIES Urinary catecholamine and VMA excretion, serum urea and creatinine, ECG, chest X-ray and intravenous pyelography were normal. Studies of thyroid function gave the following results: Serum TSH 60 pU/ml (normal 0-4 pU/ml), T3 resin uptake 23.3% (normal ml 22-35c/o), serum Thyroxine 4.7 &lo0 (normal 63-14.0 pg/lOO ml), adjusted Thyroxine 3.77 pg/lOO ml (normal 6.3-14-2 pg/lOO ml). Perchlorate discharge test normal. Thyroid antibodies: Thyroglobulin haemagglutanin, 1:1600; colloidal immunofluorescence, positive 3t; microsomal haernagglutination, 1:51200; microsomal immunofluorescence, positive 3+. A percutaneous needle biopsy of the thyroid confirmed the diagnosis of Hashimoto's thyroiditis.
Other pertinent laboratory studies included the following : WR, VDRL negative, salivary gland antibody screen negative, LE cell test negative, antinuclear factor negative. Direct Coombs' test negative to S different antisera. Smooth muscle antibody negative, antimitochondrial antibody negative. Gastric antibody screen was positive Pt; Rheumatoid factor (Waaler Rose) positive 1:M but RA latex agglutination was negative. Serum IgG 2063 mg/100 ml, IgM 101 mg/100 ml and IgA 126 mg/100 ml. IgA was also detectable in saliva. Cytogenetic studies were as follows: Cells derived by culture of peripheral leukocytes on three occasions and using both conventional staining and Giemsa-trypsin banding showed 46 chromosomes with an XX complement. Conventional staining showed 1 chromosome missing
124 from the E group and an extra small acrocentric chromosome midway in size between a D and a G group chromosome. Giemsa banding showed about two-thirds missing from the short arms of one of the number 18 chromosomes. All of the other chromosomes appeared normal (Figure 1). The father had died some years previously of carcinoma of colon but the mother’s karyotype was normal. The patient was treated with thyroxine replacement therapy and achieved a euthyroid status with shrinkage of the goitre.
DISCUSSION Nearly all the physical features described in this case have been reported in a considerable proportion of the ‘mild’ forms of the 18psyndrome. Many of the features of Turner’s syndrome were present in this girl. Disorders of the autoimmune system have been associated with several chromosomal disorders. There is an increased frequency of thyroiditis in isochromosome X patients (Sparkes and Motulsky, 1963) and there appears to be a familial predisposition to thyroid disease in Downs syndrome (Fiallow et nl., 1971). Ruvalcaba (1970) and Kistenmacher et al. (1973) have previously described the association of 18p- syndrome with autoimmune thyroiditis. Uchida et al. (1965) describe hypothyroidism in one further case but the nature of the hypothyroidism was not reported. Buhler et al. (1964.) also described hypothyroidism in a case but presented evidence to suggest a defect in thyroxine synthesis as the origin of the hypothyroidism. I n the case described in the current report the diagnosis of autoimmune thyroiditis was secured both histologically and serologically. IgA deficiency has been described in at least 9 cases of 18p-, including one patient with coexistent thyroiditis (Ruvalcaba, 1970). I n the current case IgA formation appeared to be normal. Rheumatoid arthritis has also been described in relationship to IgA deficiency. Two cases of 18p- syndrome have been reported to have both rheumatoid arthritis, one having IgA deficiency (Finley et al., 1972). The current case had no clinical evidence of rheumatoid arthritis but the Waaler-Rose test for rheumatoid factor was positive. The patient also had other evidence of autoimmune disease with positive
AUSTRALIAN PAEDIATRIC JOUIW~L gastric antibody titres. The association reported in this case of thyroiditis and partial deletion of the short arm of 13 chromosome in associa. tion with other evidence of autoimmune disease appears to be part of a spectrum of associa. tion of this chromosomal abnormality with immune disease, including rheumatoid arthritis, thyroiditis and IgA deficiency. The nature of this relationship remains obscure.
ACKNOWLEDGEMENTS Dr. A. Warren, Superintendent, Auckland Hospital, kindly gave permission to publish this case. The thyroid biopsy was prepared by Professor T. K. Fraser and the chromosomal studies by Professor W. R. Centerwall, Loma Linda University, and Dr. 1). M. 0. Becroft, Auckland Hospital. P. D. Gluckman is the recipient of a fellowship of the R.M.R. Spencer Trust.
REFERENCES BUIILER,E. M., BLJHLER, U. K., and STALDER, G. R. (1964), Partial Monosomy 18 and anomaly of thyroxine synthesis, Lancet, 1: 170-171. FIALLOW, P., THULINE,H., HECHT, F., BRYANT,J . (1971), Familial predisposition to thyroid disease in Down’s syndrome; controlled immunocheniical studies, Amer. J. hum. Genet., 23: 67-85. FINLEY, S. C., FINLEY, W. H., JOHNSON, J. C., DODSON, W. H., and MCPHEE,H. T. (1972), Rheumatoid arthritis in the 46, xx, 18p- syndrome, Clin. Genet., 3: 465-469. FITZGERALD, M. (1974), The 18p- syndrome: A case report, Aust. paediat. J., 10: 371-372. GROUCHY de J. (1969), The la-, 18q- and 18r syndromes, Birth Defects, Original Articles, Series Vol. V, No. 5, p. 74. KISTENMACIIER, M. L., DIGEORGE,A. M., and PUNNETT, H. H. (1973), The association of autoimmune disorders with 18p- syndrome, Amer. J. hum. Genet., 26: 49A. LLJRIE,I. W., and LAZJUK,G. I., (1972), Partial Monosomies 18, Humangenetik, 203-222. RLJVALCABA, R. H. A. (19701, Deletion of Chromosome group E. and thyroid autoimmunity, J . Pediat., 77: 343-344. SPARKES, R., and MOTULSKY,A. (1963), Hashimoto’s disease in Turner’s syndrome with iso-chromosome X, Lancet, 1: 947. UCHIDA,I. A., MCRAE,K. W., WANG,H. C., and REY, M. (1965), Familial short arm deficiency of chromosome 18 concomitant with arrhinencephaly and alopecia congenita, Amer. 1. hum. Genet., 17: 410-419.
Correspondence to P. D. Gluckman, Division of Pediatric Endocrinology, Department of Pediatrics, University of California, San Francisco, California 94143.
Autoimmune Thyroiditis in a Case of I8p- Syndrome Feltow, Department
P. D. GLUCKMAN Aucklund, Azcckknd, New Zealand
01 Pediatrics University of
Gluckman, P. D. (1977). Aust. paediat. I., 13, 122-124. Autoimmune thyroiditis in a case of 18p- syndrome. A case of a 16-year-old female with autoimmune thyroiditis and a deletion of the short arm of a chromosome 18 (46, xx, 18p-) is described. Evidence for other autoimmune phenomena was also present. The association between this chromosomal aberration and autoimmune disease is reviewed.
HASHIMOTO’S THYROIDITIS IN A CASE OF 18pDeletion of the short arm of chromosome 18 presents with a varying clinical picture ranging from mild to severe. Two major clinical patterns have emerged from the 64 cases reported in the literature (Lurie and Lazjuk, 1972, Fitzgerald, 1974, Kistenmacher et al., 1973). N‘me cases with arrhinencephaly and associated severe CNS abnormality have been reported. The majority of the other cases have shown a milder form in which the most common features are mental retardation, growth failure; orbital malformation, low set floppy ears, severe dental decay, acromicria and partial webbing of the second and third toes. In addition, many features suggestive of Turner’s Syndrome are reported. These include webbing of the neck and a shieldlike chest. Deficiency of the immunoglobin IgA has been reported in 13 cases as well as in the other abnormalities of the 18 chromosome, 18q- and 18r. Lurie and Lazjuk (1972) report 8 cases of endocrinopathy in a review of 62 cases but details have only been published in 4 cases, 2 being described as hypothyroid, one of whom had thyroiditis. Kistenmacher et al. (1973) describe one additional case with diabetes, autoimmune thyroiditis and possible Sjogren’s syndrome. This report describes a further case of 18p- syndrome with associated autoimmune thyroiditis. CASE REPORT The propositus, a 17-year-old Caucasian female was the product of a pregnancy comReceived November 25, 1976.
plicated by hypertension, delivered following surgical induction at 36 week gestation, and weighed 2,750 gm. At the time of delivery the maternal age was 30 and paternal age 36. Mother’s first pregnancy terminated with a stillbirth with no apparent physical stigmata, and there had been one spontaneous abortion. There were 2 normal younger siblings. The neonatal course was complicated by mild respiratory distress. She appeared to have normal development in the first year of life, but when at 18 months she was admitted to hospital with meningitis it was noted that she was not yet walking on her own. By the age of 5 years psychomotor retardation was obvious and she later attended a special school for intelIectually impaired children. At the age of 16 she was referred for evaluation of a goitre first noticed at the age of 13, in association with symptoms of hypothyroidism. There was no history of joint disease. At that time her height was 140 cm (11 cm below 3rd centile), weight 40 kg (10th centile), head circumference 58.5 cm (40th centile) . She was overtly hypothyroid with a diffusely enlarged firm thyroid weighing about 80 g. Other physical features were a low nuchal hairline, short webbed neck, irregular poor dentition with multiple caries, bilateral ptosis, large floppy ears, and short fingers and toes, particularly the 4th and 5th metacarpals. Her B.P. was 130/90; there was no evidence of aortic coarctation, no cardiomegaly and there was a grade 2/4 ejection systolic murmur at the left sternal edge. Puberty was complete. Skeletal survey demonstrated a thoracolumbar scoliosis, 6 lumbar vertebrae and spina bifida occulta of the 6th vertebra.
123
5
IGROUP A)
(GROUP 6 )
FIGURE 1: Karyotypc of a trypsin G-handed cell from the patient.
LABORATORY STUDIES Urinary catecholamine and VMA excretion, serum urea and creatinine, ECG, chest X-ray and intravenous pyelography were normal. Studies of thyroid function gave the following results: Serum TSH 60 pU/ml (normal 0-4 pU/ml), T3 resin uptake 23.3% (normal ml 22-35c/o), serum Thyroxine 4.7 &lo0 (normal 63-14.0 pg/lOO ml), adjusted Thyroxine 3.77 pg/lOO ml (normal 6.3-14-2 pg/lOO ml). Perchlorate discharge test normal. Thyroid antibodies: Thyroglobulin haemagglutanin, 1:1600; colloidal immunofluorescence, positive 3t; microsomal haernagglutination, 1:51200; microsomal immunofluorescence, positive 3+. A percutaneous needle biopsy of the thyroid confirmed the diagnosis of Hashimoto's thyroiditis.
Other pertinent laboratory studies included the following : WR, VDRL negative, salivary gland antibody screen negative, LE cell test negative, antinuclear factor negative. Direct Coombs' test negative to S different antisera. Smooth muscle antibody negative, antimitochondrial antibody negative. Gastric antibody screen was positive Pt; Rheumatoid factor (Waaler Rose) positive 1:M but RA latex agglutination was negative. Serum IgG 2063 mg/100 ml, IgM 101 mg/100 ml and IgA 126 mg/100 ml. IgA was also detectable in saliva. Cytogenetic studies were as follows: Cells derived by culture of peripheral leukocytes on three occasions and using both conventional staining and Giemsa-trypsin banding showed 46 chromosomes with an XX complement. Conventional staining showed 1 chromosome missing
124 from the E group and an extra small acrocentric chromosome midway in size between a D and a G group chromosome. Giemsa banding showed about two-thirds missing from the short arms of one of the number 18 chromosomes. All of the other chromosomes appeared normal (Figure 1). The father had died some years previously of carcinoma of colon but the mother’s karyotype was normal. The patient was treated with thyroxine replacement therapy and achieved a euthyroid status with shrinkage of the goitre.
DISCUSSION Nearly all the physical features described in this case have been reported in a considerable proportion of the ‘mild’ forms of the 18psyndrome. Many of the features of Turner’s syndrome were present in this girl. Disorders of the autoimmune system have been associated with several chromosomal disorders. There is an increased frequency of thyroiditis in isochromosome X patients (Sparkes and Motulsky, 1963) and there appears to be a familial predisposition to thyroid disease in Downs syndrome (Fiallow et nl., 1971). Ruvalcaba (1970) and Kistenmacher et al. (1973) have previously described the association of 18p- syndrome with autoimmune thyroiditis. Uchida et al. (1965) describe hypothyroidism in one further case but the nature of the hypothyroidism was not reported. Buhler et al. (1964.) also described hypothyroidism in a case but presented evidence to suggest a defect in thyroxine synthesis as the origin of the hypothyroidism. I n the case described in the current report the diagnosis of autoimmune thyroiditis was secured both histologically and serologically. IgA deficiency has been described in at least 9 cases of 18p-, including one patient with coexistent thyroiditis (Ruvalcaba, 1970). I n the current case IgA formation appeared to be normal. Rheumatoid arthritis has also been described in relationship to IgA deficiency. Two cases of 18p- syndrome have been reported to have both rheumatoid arthritis, one having IgA deficiency (Finley et al., 1972). The current case had no clinical evidence of rheumatoid arthritis but the Waaler-Rose test for rheumatoid factor was positive. The patient also had other evidence of autoimmune disease with positive
AUSTRALIAN PAEDIATRIC JOUIW~L gastric antibody titres. The association reported in this case of thyroiditis and partial deletion of the short arm of 13 chromosome in associa. tion with other evidence of autoimmune disease appears to be part of a spectrum of associa. tion of this chromosomal abnormality with immune disease, including rheumatoid arthritis, thyroiditis and IgA deficiency. The nature of this relationship remains obscure.
ACKNOWLEDGEMENTS Dr. A. Warren, Superintendent, Auckland Hospital, kindly gave permission to publish this case. The thyroid biopsy was prepared by Professor T. K. Fraser and the chromosomal studies by Professor W. R. Centerwall, Loma Linda University, and Dr. 1). M. 0. Becroft, Auckland Hospital. P. D. Gluckman is the recipient of a fellowship of the R.M.R. Spencer Trust.
REFERENCES BUIILER,E. M., BLJHLER, U. K., and STALDER, G. R. (1964), Partial Monosomy 18 and anomaly of thyroxine synthesis, Lancet, 1: 170-171. FIALLOW, P., THULINE,H., HECHT, F., BRYANT,J . (1971), Familial predisposition to thyroid disease in Down’s syndrome; controlled immunocheniical studies, Amer. J. hum. Genet., 23: 67-85. FINLEY, S. C., FINLEY, W. H., JOHNSON, J. C., DODSON, W. H., and MCPHEE,H. T. (1972), Rheumatoid arthritis in the 46, xx, 18p- syndrome, Clin. Genet., 3: 465-469. FITZGERALD, M. (1974), The 18p- syndrome: A case report, Aust. paediat. J., 10: 371-372. GROUCHY de J. (1969), The la-, 18q- and 18r syndromes, Birth Defects, Original Articles, Series Vol. V, No. 5, p. 74. KISTENMACIIER, M. L., DIGEORGE,A. M., and PUNNETT, H. H. (1973), The association of autoimmune disorders with 18p- syndrome, Amer. J. hum. Genet., 26: 49A. LLJRIE,I. W., and LAZJUK,G. I., (1972), Partial Monosomies 18, Humangenetik, 203-222. RLJVALCABA, R. H. A. (19701, Deletion of Chromosome group E. and thyroid autoimmunity, J . Pediat., 77: 343-344. SPARKES, R., and MOTULSKY,A. (1963), Hashimoto’s disease in Turner’s syndrome with iso-chromosome X, Lancet, 1: 947. UCHIDA,I. A., MCRAE,K. W., WANG,H. C., and REY, M. (1965), Familial short arm deficiency of chromosome 18 concomitant with arrhinencephaly and alopecia congenita, Amer. 1. hum. Genet., 17: 410-419.
Correspondence to P. D. Gluckman, Division of Pediatric Endocrinology, Department of Pediatrics, University of California, San Francisco, California 94143.
