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Graves' disease in patients with 22q11.2 deletion
Graves’ disease in patients with 22q11.2 deletion Hiroshi Kawame, MD, Masanori Adachi, MD, Katsuhiko Tachibana, MD, Kenji Kurosawa, MD, Fumiyuki Ito, MD, Marie M. Gleason, MD, Stuart Weinzimer, MD, Lorraine Levitt-Katz, MD, Kathleen Sullivan, MD, PhD, and Donna M. McDonald-McGinn, MS, CGC We report 4 female patients and 1 male patient with a 22q11.2 deletion and Graves’ disease diagnosed at age 27 months, 7, 10, 17, and 16 years, respectively. The clinical presentations were typical for hyperthyroidism, but 1 female infant had seizures in addition to symptoms of hyperthyroidism. All patients had elevated serum levels of thyroid hormones in association with suppressed thyroid-stimulating hormone levels. From these observations, we suggest that Graves’ disease may be a part of the clinical spectrum associated with the 22q11.2 deletion syndrome. (J Pediatr 2001;139:892–5)
The chromosome 22q11.2 deletion syndrome has an extremely wide phenotypic spectrum.1 This diagnosis is the most common microdeletion syndrome, with an estimated incidence of 1 in 3000 to 4000 live births.2 Manifestations associated with this syndrome involve many organ systems, typically consisting of conotruncal cardiac abnormalities, hypoparathyroidism, developmental delay, and immunodeficiency. The frequency of autoimmune disease is reported to be increased in patients with a 22q11.2 deletion.1 Graves’ disease is the most common cause of thyrotoxicosis in childhood and adolescence and is an autoimmune thyroid disease characterized by the production of stimulating antibodies to the thyrotrophic hormone receptor.3 Ap-
proximately 95% of all patients with Graves’ disease are older than 15 years of age. The pathogenesis of Graves’ disease is thought to involve a complex interaction between genetic predisposing factors and environmental triggering factors.3 Several studies have shown that there is an association of some human leukocyte antigen types and Graves’ disease susceptibility. We present 5 patients with an association of the 22q11.2 deletion and Graves’ disease.
CLINICAL REPORTS Patient Reports PATIENT 1. Patient 1 was a 19-year-old Japanese female born at 40 weeks’ gestation. Her birth weight was 2980 g,
From the Division of Clinical and Molecular Genetics, Shinshu University Hospital, Nagano, the Division of Endocrinology and Metabolism, the Division of Medical Genetics, Kanagawa Children’s Medical Center, Kanagawa, the Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan, the Division of Cardiology, the Division of Endocrinology, the Division of Immunologic and Infectious Disease, the Division of Human Genetics and Molecular Biology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.
Submitted for publication Feb 1, 2001; revision received June 20, 2001; accepted Aug 9, 2001. Reprint requests: Hiroshi Kawame, MD, Division of Clinical and Molecular Genetics, Department of Hygiene and Medical Genetics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano 390-8621, Japan. Copyright © 2001 by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/22/119448 doi:10.1067/mpd.2001.119448
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and her length was 47 cm. She had a submucosal cleft palate and hypernasal speech. The submucosal cleft palate was surgically repaired when she was 4 years of age. In infancy she had speech delay, although she had no formal developmental assessment. She attended regular schools but had borderline mental retardation. She experienced decreased activity and refused to go to school for a couple of years. At age 17 years and 7 months, she experienced body weight loss and excessive sweating. Two months later she had hand tremors, diffuse goiter, exophthalmos, and hypertension and was given the diagnosis of Graves’ disease, which was managed with methimazole (30 mg/d), and her symptoms improved. At age 18 years she had her first seizures and was subsequently given the diagnosis of hypoparathyroidism (serum Ca2+: 4.2 mg/dL). She was treated with alfacalcidol. On examination at 19 years of age, her weight was 52 kg (the mean in Japan), and her height was 148.5 cm (–1.9 SD). She had hooded eyelids, short palpebral fissures, boxlike nose, and hypoplastic alae nasi. She had slender fingers and a palpable diffuse goiter. Her brain computed tomography revealed calcification in the basal ganglia but no structural anomalies. Her electroencephalogram showed sharp waves and spikes. MMI PTU TSH
Methimazole Propylthiouracil Thyroid-stimulating hormone
PATIENT 2. Patient 2 was a 20-year-old Japanese female. She was born at 40 weeks’ gestation with a birth weight of 2180 g and a length of 45 cm. At birth
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THE JOURNAL OF PEDIATRICS
VOLUME 139, NUMBER 6 Table. Summary of clinical findings and thyroid function of the patients
Patient 1 Age at onset Symptoms Goiter Laboratory data TSH (µU/mL) T3 (ng/mL) T4 (µg/dL) fT3 (pg/mL) fT4 (ng/dL) TRAb (%) TSAb (%) TPOAb (U/mL) Microsomal antibody Thyroglobulin antibody Therapy Platelet count (104) PAIgG (ng/107 cells)
Patient 2
Patient 3
Patient 4
17 years 10 years Tremor, weight loss, Tachycardia, exophthalmos excess sweating + +
7 years Tachycardia, polyuria +
16 years 27 months Tachycardia, Seizures, fatigue tachycardia +
0.03 NA NA 26.3 9.4 39 NA 3.2 NA 100 MMI 11.7 Negative
<0.1 5.5 25.5 NA 10.2 13.7 4.0 µU/mL† NA 1600 <100 MMI/PTU 8.8 12.6
<0.03 2.06 10.64 6.68 2.56 3.4 110 NA 400 <100 MMI 16.4 NA
<0.1 2.6 18.6 NA 4 35.1 NA NA <100 <100 MMI/PTU 8.5 51.6
Normal value
Patient 5
<0.005 NA 23.5 NA NA 62* NA NA Negative Negative MMI/PTU NA NA
0.34 - 3.5 0.8 - 1.8 4.6 - 12.6 2.4 - 4.3 0.97 - 1.79 <15 <180 <0.3 <100 <100
9.0 - 25
NA, Not available; TRAb, thyroid-stimulating hormone receptor antibody; TSAb, thyroid-stimulating hormone receptor stimulating antibody; TPOAb, thyroid peroxidase antibody; PAIgG, platelet-associated immunoglobulin G. *Normal value: <10. †Normal value: <0.3 µU/mL.
she was noted to have Tetralogy of Fallot, which was surgically corrected at 2 years and 7 months. At age 3 years she was given the diagnosis of velopharyngeal incompetence because of her hypernasal speech, and a pharyngeal flap surgery was performed at age 5 years. At 10 years of age, she was admitted to our center for evaluation of hypocalcemia. At the same time she was noted to have an increased thyroid hormone level and was given the diagnosis of Graves’ disease. Retrospectively, she had tachycardia at rest and excessive sweating. On examination her weight was 51.7 kg (mean), and her height was 152.5 cm (–1.1 SD). Her face appeared long. She had hooded eyelids, boxlike nose, hypoplastic alae nasi, and a small mouth. Her fingers were slender. Her full-scale Wechsler Intelligence Scale for Children IQ was 70. Her brain computed tomography demonstrated mild atrophy of the cerebellum. She was initially treated with MMI, but she devel-
oped a rash and was subsequently treated with propylthiouracil. PATIENT 3. Patient 3 was a 15-year-old Japanese girl. She was born to nonconsanguineous parents at 39 weeks’ gestation with a birth weight of 2700 g and a length of 43.5 cm. The mother, now 40 years of age, had Graves’ disease, which was managed with subtotal thyroidectomy when she was 37 years old. The father had an episode of idiopathic thrombocytopenic purpura at the age of 29 years. When the patient was 18 months, hypocalcemia developed. She had velopharyngeal incompetence with hypernasal speech, which was surgically repaired at the age of 5 years. At age 7 years she had tachycardia and polyuria and subsequently was given the diagnosis of Graves’ disease. Initially she was treated by MMI, but later with PTU because of leukopenia. On examination at age 15 years, her weight was 36.4 kg (–2.0 SD), and her height
was 146 cm (–2.1 SD). She had hooded eyelids, boxlike nose, hypoplastic alae nasi, and malar hypoplasia. She had bilateral overlapping second and third toes. Her full-scale Tanaka-Binnet IQ was 60. Recently her Graves’ disease relapsed, and she has continued to be treated with a higher dose of PTU (100 mg/d). Patients 2 and 3 were subjects in a previous report.4 PATIENT 4. Patient 4 was a 17-year-old Japanese boy. He was born to nonconsanguineous parents at 38 weeks’ gestation. His birth weight was 2600 g, and his length was 46 cm. He was noted to have Tetralogy of Fallot, which was corrected at the age of 6 years. He had carpopedal spasm at age 12 years and was given the diagnosis of hypoparathyroidism (serum Ca2+: 5.3 mg/dL). He was subsequently treated with alfacalcidol, and hypocalcemia was resolved by age 15 years. At age 13 years, during admission for manage893
KAWAME ET AL
ment of hypocalcemia, he had paranoid psychotic symptoms and was given the diagnosis of schizophrenia. At the age of 15 years, he was hospitalized for 6 months because of his schizophrenia. At age 16 years he had tachycardia, palpitation, general fatigue, and difficulty breathing and was given the diagnosis of Graves’ disease. On examination, his weight was 45.7 kg (–1.6 SD), and his height was 152.8 cm (–3.0 SD). He had hooded eyelids, short palpebral fissures, and boxlike nose and strabismus. He had a moderate scoliosis. He had no palpable goiter, but his thyroid gland was smoothly enlarged by ultrasound examination. He was initially treated with PTU, propranolol, and saturated potassium iodide (Lugol’s solution), and his symptoms of hyperthyroidism improved remarkably. He has continued to be treated with MMI (5 mg/d). PATIENT 5. Patient 5 was a 31-monthold adopted Caucasian. Her birth weight was 2795 g. At birth, she was found to have a bicuspid aortic valve, a conoseptal hypoplasia type ventricular septal defect, and interrupted aortic arch type B with aberrant right subclavian artery. Heart surgery was performed on day 9 of life. Early hypocalcemia caused by hypoparathyroidism required calcium supplementation for the first few months of life. She had bilateral hydronephoresis and recurrent urinary tract infections. At 15 months of age she had unusual staring episodes after a painful stimulus. These were believed to be “breath-holding” spells. Her cardiac status was stable, with moderate left ventricular outflow obstruction. At 25 months of age she had a spell associated with a seizure, and sinus tachycardia was noted. At 27 months of age, the spells increased in frequency, and several generalized seizures occurred. She was treated with phenytoin. An electroencephalogram was negative. Baseline sinus tachycardia at rates of 160 to 190 beats/min, which was unremitting, was noted, and thyroid function tests were sent as part 894
THE JOURNAL OF PEDIATRICS DECEMBER 2001 of the workup for her tachycardia and irritability. In retrospect, the family believed that over a period of months before the diagnosis, they had noticed regression in her development, increased irritability, jitteriness, increased hypotonia, diarrhea, and poor weight gain despite an increased appetite. On admission she was restless and somewhat irritable. She had a resting tachycardia (heart rate ~ 160). Her height was 91.9 cm (+1.2 SD), and her weight was 12.7 kg (+0.3 SD). Her thyroid gland was diffusely and symmetrically enlarged, approximately 3.5 3.5 cm2 per lobe. The consistency of the gland was smooth, rubbery, and non-nodular. She had a harsh 3-4/6 systolic murmur along the left sternal border. She had brisk reflexes and mild tremors. She was given the diagnosis of Graves’ disease, which was confirmed by laboratory tests. A roentgenogram of the hand revealed an advanced skeletal age of 39 months. She was treated with MMI (0.8 mg/kg/day) and propranolol (2 mg/kg/day). A pruritic rash developed, and PTU was substituted. She initially had marked improvement, both clinically and biochemically, but continued to require very large doses of PTU (11 to 12 mg/kg/day) to control her hyperthyroidism. She subsequently failed medical therapy and required total thyroidectomy.
Endocrine and Other Findings Thyroid function tests at the time of diagnosis of Graves’ disease for the patients are shown in the Table. All 5 patients had elevated serum levels of thyroid hormones in association with suppressed levels of thyroid-stimulating hormone. TSH-receptor antibodies were positive in 3 female patients (patients 1, 2, and 5), and other characteristic anti-thyroid antibodies such as anti-thyroglobulin and anti-microsomal antibodies were positive in 3 patients (patients 1, 3, and 4). All patients had a very mild decrease of CD3 T-cell number, and 1 patient (patient 3) had a mild decrease of T-cell responses to mito-
gens, but none of our 5 patients had normal-range CD8 cell numbers. All patients were shown to have a deletion 22q11.2 detected by fluorescence in situ hybridization analysis with N25 (D22S75) or TUPLE1 probes.
DISCUSSION We report on 5 patients with the 22q11.2 deletion syndrome, confirmed by fluorescence in situ hybridization analysis, who were found to have Graves’ disease. Patients 1, 3, and 5 clearly had Graves’ disease by the laboratory results, but the diagnosis of Graves’ disease in patient 4 was tentative because of a mild increase in thyroid hormone level and a lack of TSH-receptor antibodies. It is noteworthy that all the patients had mild thrombocytopenia, and 2 of the 5 patients showed elevated anti-platelet antibodies (platelet-associated–immunoglobulin G). Patient 5 had an unusual clinical presentation because of the very early age at onset and atypical initial symptoms. Clinicians should be aware of the possibility of Graves disease in patients with a 22q11 deletion at any age. Autoimmune disorders have been described in patients with DiGeorge syndrome/veleocardiofacial syndrome. A single case report of a 13-year-old patient given the clinical diagnosis of DiGeorge syndrome has been reported to have an autoimmune thyroiditis (Graves’ disease).5 The karyotype of this patient was reported to be mosaicism for a deletion of chromosome 22q, although fluorescence in situ hybridization analysis was not available at that time. Recently Kawamura et al6 reported an 18-year-old female patient with partial DiGeorge syndrome and Graves’ disease. This patient was shown to have a deletion of 22q11.2 by fluorescence in situ hybridization analysis.6 Furthermore autoimmune hemolytic anemia,7,8 immune thrombocytopenia,7,9 recurrent immune cytopenia,8 and juvenile rheumatoid arthritis or polyarthritis
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VOLUME 139, NUMBER 6 have been described in patients with a 22q11.2 deletion.10 Our cases, along with previously described patients, lead us to suggest that this syndrome is associated with a predisposition to autoimmune disorders. The mechanism of predisposition to autoimmune diseases in the 22q11.2 deletion syndrome remains unknown. Several candidate genes, including the TSH receptor gene for nonautoimmune hyperthyroidism, that have been associated with Graves’ disease are reported, 3 but none of those genes is located in the chromosome 22q11 region. The literature has suggested that the defect of T-cell function might predispose to immune dysregulation and autoimmune diseases.11 We speculate that impaired T-cell differentiation or T-cell regulatory dysfunction may lead to the development of autoimmune diseases regardless of clinical immunodeficiency, documented T-cell dysfunction, or both. Although we did not perform human leukocyte antigen typing as a risk factor for Graves’ disease, Sullivan et al10 did confirm predisposing human leukocyte antigen types in her patients with juvenile rheumatoid arthritis and the 22q11.2 deletion. In addition, it has been shown that other genetic susceptibilities may contribute to the development of autoimmune diseases. We hypothesize that the combination of T-cell dysfunction, genetic susceptibilities, and appropriate environmental triggers can precipitate autoimmune disease in some patients with a 22q11.2 deletion syndrome. Consequently, autoimmune diseases overall are uncommon manifestations of the syndrome. We propose that the association between the 22q11.2 deletion and the de-
velopment of Graves’ disease is not a coincidence. First, the incidence of Graves’ disease in the general population has been estimated to be 17.7 in 100,000.12 Because 1 in 352 patients with the 22q11.2 deletion syndrome evaluated at The Children’s Hospital, Philadelphia, had Graves’ disease, the incidence of Graves’ disease in this population was approximately 16 times that seen in the general population. Second, patient 5 showed a very unusual presentation in terms of age at onset of Graves’ disease. Graves’ disease in children younger than 4 years is very rare. Finally, Graves’ disease, including autoimmune thyroid disease, is much less frequent in males; however, one of our patients was a male. Based on our findings, we suggest that Graves’ disease is an uncommon but significant manifestation of the 22q11.2 deletion syndrome. Evaluation of thyroid hormone function is indicated in patients with the syndrome and suggestive features of hyperthyroidism. Our observation and the literature are consistent with the theory that the 22q11.2 microdeletion syndrome is associated with a predisposition to autoimmune disorders, which contributes to the extremely variable phenotypes of affected patients.
REFERENCES 1. McDonald-McGinn DM, Kirschner R, Goldmuntz E, Sullivan K, Eicher P, Gerdes M, et al. The Philadelphia story: the 22q11.2 deletion: report on 250 patients. Genet Couns 1999;10:11-24. 2. Goodship J, Cross I, Liling J, Wren C. A population study of chromosome 22q11 deletions in infancy. Arch Dis Child 1998;79:348-51.
3. Zimmerman D, Lteif AN. Thyrotoxicosis in children. Endocrinol Metab Clin North Am 1998;27:109-25. 4. Adachi M, Tachibana K, Masuno M, Makita Y, Maesaka H, Okada T, et al. Clinical characteristics of children with hypoparathyroidism due to 22q11.2 microdeletion. Eur J Pediatr 1998;157:34-8. 5. Ham Pong AJ, Cavallo A, Holman GH, Goldman AS. DiGeorge syndrome: long-term survival complicated by Graves’ disease. J Pediatr 1985;106: 619-20. 6. Kawamura T, Nimura I, Hanafusa M, Fujikawa R, Okubo M, Egusa G, et al. DiGeorge syndrome with Graves’ disease: a case report. Endocr J 2000; 47:91-5. 7. Pinchas-Hamiel O, Mandel M, Engelberg S, Passwell JH. Immune hemolytic anemia, thrombocytopenia and liver disease in patient with DiGeorge syndrome. Isr J Med Sci 1994;30:530-2. 8. DePiero AD, Lourie EM, Berman BW, Robin NH, Zinn AB, Hostoffer RW. Recurrent immune cytopenias in two patients with DiGeorge/velocardiofacial syndrome. J Pediatr 1997;131:484-6. 9. Levy A, Michel G, Lemerrer M, Philip A. Idiopathic thrombocytopenia purpura in two mothers of children with DiGeorge sequence: a new component manifestation of deletion 22q11? Am J Med Genet 1997;69:356-9. 10. Sullivan KE, McDonald-McGinn DM, Driscoll DA, Zmijewski CM, Ellabban AS, Reed L, et al. Juvenile rheumatoid arthritis-like polyarthritis in chromosome 22q11.2 deletion syndrome (DiGeorge anomaly/velocardiofacial syndrome/ conotruncal anomaly face syndrome). Arthritis Rheum 1997;40:430-6. 11. Etzioni A, Pollack S. Autoimmune phenomena in DiGeorge Syndrome. Isr J Med Sci 1994;30:853. 12. Berglund J, Christensen SB, Hallengren B. Total and age-specific incidence of Graves’ thyrotoxicosis, toxic nodular goiter and solitary toxic adenoma in Malmo 1970-74. J Intern Med 1990; 227:137-41.
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The chromosome 22q11.2 deletion syndrome has an extremely wide phenotypic spectrum.1 This diagnosis is the most common microdeletion syndrome, with an estimated incidence of 1 in 3000 to 4000 live births.2 Manifestations associated with this syndrome involve many organ systems, typically consisting of conotruncal cardiac abnormalities, hypoparathyroidism, developmental delay, and immunodeficiency. The frequency of autoimmune disease is reported to be increased in patients with a 22q11.2 deletion.1 Graves’ disease is the most common cause of thyrotoxicosis in childhood and adolescence and is an autoimmune thyroid disease characterized by the production of stimulating antibodies to the thyrotrophic hormone receptor.3 Ap-
proximately 95% of all patients with Graves’ disease are older than 15 years of age. The pathogenesis of Graves’ disease is thought to involve a complex interaction between genetic predisposing factors and environmental triggering factors.3 Several studies have shown that there is an association of some human leukocyte antigen types and Graves’ disease susceptibility. We present 5 patients with an association of the 22q11.2 deletion and Graves’ disease.
CLINICAL REPORTS Patient Reports PATIENT 1. Patient 1 was a 19-year-old Japanese female born at 40 weeks’ gestation. Her birth weight was 2980 g,
From the Division of Clinical and Molecular Genetics, Shinshu University Hospital, Nagano, the Division of Endocrinology and Metabolism, the Division of Medical Genetics, Kanagawa Children’s Medical Center, Kanagawa, the Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan, the Division of Cardiology, the Division of Endocrinology, the Division of Immunologic and Infectious Disease, the Division of Human Genetics and Molecular Biology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.
Submitted for publication Feb 1, 2001; revision received June 20, 2001; accepted Aug 9, 2001. Reprint requests: Hiroshi Kawame, MD, Division of Clinical and Molecular Genetics, Department of Hygiene and Medical Genetics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano 390-8621, Japan. Copyright © 2001 by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/22/119448 doi:10.1067/mpd.2001.119448
892
and her length was 47 cm. She had a submucosal cleft palate and hypernasal speech. The submucosal cleft palate was surgically repaired when she was 4 years of age. In infancy she had speech delay, although she had no formal developmental assessment. She attended regular schools but had borderline mental retardation. She experienced decreased activity and refused to go to school for a couple of years. At age 17 years and 7 months, she experienced body weight loss and excessive sweating. Two months later she had hand tremors, diffuse goiter, exophthalmos, and hypertension and was given the diagnosis of Graves’ disease, which was managed with methimazole (30 mg/d), and her symptoms improved. At age 18 years she had her first seizures and was subsequently given the diagnosis of hypoparathyroidism (serum Ca2+: 4.2 mg/dL). She was treated with alfacalcidol. On examination at 19 years of age, her weight was 52 kg (the mean in Japan), and her height was 148.5 cm (–1.9 SD). She had hooded eyelids, short palpebral fissures, boxlike nose, and hypoplastic alae nasi. She had slender fingers and a palpable diffuse goiter. Her brain computed tomography revealed calcification in the basal ganglia but no structural anomalies. Her electroencephalogram showed sharp waves and spikes. MMI PTU TSH
Methimazole Propylthiouracil Thyroid-stimulating hormone
PATIENT 2. Patient 2 was a 20-year-old Japanese female. She was born at 40 weeks’ gestation with a birth weight of 2180 g and a length of 45 cm. At birth
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THE JOURNAL OF PEDIATRICS
VOLUME 139, NUMBER 6 Table. Summary of clinical findings and thyroid function of the patients
Patient 1 Age at onset Symptoms Goiter Laboratory data TSH (µU/mL) T3 (ng/mL) T4 (µg/dL) fT3 (pg/mL) fT4 (ng/dL) TRAb (%) TSAb (%) TPOAb (U/mL) Microsomal antibody Thyroglobulin antibody Therapy Platelet count (104) PAIgG (ng/107 cells)
Patient 2
Patient 3
Patient 4
17 years 10 years Tremor, weight loss, Tachycardia, exophthalmos excess sweating + +
7 years Tachycardia, polyuria +
16 years 27 months Tachycardia, Seizures, fatigue tachycardia +
0.03 NA NA 26.3 9.4 39 NA 3.2 NA 100 MMI 11.7 Negative
<0.1 5.5 25.5 NA 10.2 13.7 4.0 µU/mL† NA 1600 <100 MMI/PTU 8.8 12.6
<0.03 2.06 10.64 6.68 2.56 3.4 110 NA 400 <100 MMI 16.4 NA
<0.1 2.6 18.6 NA 4 35.1 NA NA <100 <100 MMI/PTU 8.5 51.6
Normal value
Patient 5
<0.005 NA 23.5 NA NA 62* NA NA Negative Negative MMI/PTU NA NA
0.34 - 3.5 0.8 - 1.8 4.6 - 12.6 2.4 - 4.3 0.97 - 1.79 <15 <180 <0.3 <100 <100
9.0 - 25
NA, Not available; TRAb, thyroid-stimulating hormone receptor antibody; TSAb, thyroid-stimulating hormone receptor stimulating antibody; TPOAb, thyroid peroxidase antibody; PAIgG, platelet-associated immunoglobulin G. *Normal value: <10. †Normal value: <0.3 µU/mL.
she was noted to have Tetralogy of Fallot, which was surgically corrected at 2 years and 7 months. At age 3 years she was given the diagnosis of velopharyngeal incompetence because of her hypernasal speech, and a pharyngeal flap surgery was performed at age 5 years. At 10 years of age, she was admitted to our center for evaluation of hypocalcemia. At the same time she was noted to have an increased thyroid hormone level and was given the diagnosis of Graves’ disease. Retrospectively, she had tachycardia at rest and excessive sweating. On examination her weight was 51.7 kg (mean), and her height was 152.5 cm (–1.1 SD). Her face appeared long. She had hooded eyelids, boxlike nose, hypoplastic alae nasi, and a small mouth. Her fingers were slender. Her full-scale Wechsler Intelligence Scale for Children IQ was 70. Her brain computed tomography demonstrated mild atrophy of the cerebellum. She was initially treated with MMI, but she devel-
oped a rash and was subsequently treated with propylthiouracil. PATIENT 3. Patient 3 was a 15-year-old Japanese girl. She was born to nonconsanguineous parents at 39 weeks’ gestation with a birth weight of 2700 g and a length of 43.5 cm. The mother, now 40 years of age, had Graves’ disease, which was managed with subtotal thyroidectomy when she was 37 years old. The father had an episode of idiopathic thrombocytopenic purpura at the age of 29 years. When the patient was 18 months, hypocalcemia developed. She had velopharyngeal incompetence with hypernasal speech, which was surgically repaired at the age of 5 years. At age 7 years she had tachycardia and polyuria and subsequently was given the diagnosis of Graves’ disease. Initially she was treated by MMI, but later with PTU because of leukopenia. On examination at age 15 years, her weight was 36.4 kg (–2.0 SD), and her height
was 146 cm (–2.1 SD). She had hooded eyelids, boxlike nose, hypoplastic alae nasi, and malar hypoplasia. She had bilateral overlapping second and third toes. Her full-scale Tanaka-Binnet IQ was 60. Recently her Graves’ disease relapsed, and she has continued to be treated with a higher dose of PTU (100 mg/d). Patients 2 and 3 were subjects in a previous report.4 PATIENT 4. Patient 4 was a 17-year-old Japanese boy. He was born to nonconsanguineous parents at 38 weeks’ gestation. His birth weight was 2600 g, and his length was 46 cm. He was noted to have Tetralogy of Fallot, which was corrected at the age of 6 years. He had carpopedal spasm at age 12 years and was given the diagnosis of hypoparathyroidism (serum Ca2+: 5.3 mg/dL). He was subsequently treated with alfacalcidol, and hypocalcemia was resolved by age 15 years. At age 13 years, during admission for manage893
KAWAME ET AL
ment of hypocalcemia, he had paranoid psychotic symptoms and was given the diagnosis of schizophrenia. At the age of 15 years, he was hospitalized for 6 months because of his schizophrenia. At age 16 years he had tachycardia, palpitation, general fatigue, and difficulty breathing and was given the diagnosis of Graves’ disease. On examination, his weight was 45.7 kg (–1.6 SD), and his height was 152.8 cm (–3.0 SD). He had hooded eyelids, short palpebral fissures, and boxlike nose and strabismus. He had a moderate scoliosis. He had no palpable goiter, but his thyroid gland was smoothly enlarged by ultrasound examination. He was initially treated with PTU, propranolol, and saturated potassium iodide (Lugol’s solution), and his symptoms of hyperthyroidism improved remarkably. He has continued to be treated with MMI (5 mg/d). PATIENT 5. Patient 5 was a 31-monthold adopted Caucasian. Her birth weight was 2795 g. At birth, she was found to have a bicuspid aortic valve, a conoseptal hypoplasia type ventricular septal defect, and interrupted aortic arch type B with aberrant right subclavian artery. Heart surgery was performed on day 9 of life. Early hypocalcemia caused by hypoparathyroidism required calcium supplementation for the first few months of life. She had bilateral hydronephoresis and recurrent urinary tract infections. At 15 months of age she had unusual staring episodes after a painful stimulus. These were believed to be “breath-holding” spells. Her cardiac status was stable, with moderate left ventricular outflow obstruction. At 25 months of age she had a spell associated with a seizure, and sinus tachycardia was noted. At 27 months of age, the spells increased in frequency, and several generalized seizures occurred. She was treated with phenytoin. An electroencephalogram was negative. Baseline sinus tachycardia at rates of 160 to 190 beats/min, which was unremitting, was noted, and thyroid function tests were sent as part 894
THE JOURNAL OF PEDIATRICS DECEMBER 2001 of the workup for her tachycardia and irritability. In retrospect, the family believed that over a period of months before the diagnosis, they had noticed regression in her development, increased irritability, jitteriness, increased hypotonia, diarrhea, and poor weight gain despite an increased appetite. On admission she was restless and somewhat irritable. She had a resting tachycardia (heart rate ~ 160). Her height was 91.9 cm (+1.2 SD), and her weight was 12.7 kg (+0.3 SD). Her thyroid gland was diffusely and symmetrically enlarged, approximately 3.5 3.5 cm2 per lobe. The consistency of the gland was smooth, rubbery, and non-nodular. She had a harsh 3-4/6 systolic murmur along the left sternal border. She had brisk reflexes and mild tremors. She was given the diagnosis of Graves’ disease, which was confirmed by laboratory tests. A roentgenogram of the hand revealed an advanced skeletal age of 39 months. She was treated with MMI (0.8 mg/kg/day) and propranolol (2 mg/kg/day). A pruritic rash developed, and PTU was substituted. She initially had marked improvement, both clinically and biochemically, but continued to require very large doses of PTU (11 to 12 mg/kg/day) to control her hyperthyroidism. She subsequently failed medical therapy and required total thyroidectomy.
Endocrine and Other Findings Thyroid function tests at the time of diagnosis of Graves’ disease for the patients are shown in the Table. All 5 patients had elevated serum levels of thyroid hormones in association with suppressed levels of thyroid-stimulating hormone. TSH-receptor antibodies were positive in 3 female patients (patients 1, 2, and 5), and other characteristic anti-thyroid antibodies such as anti-thyroglobulin and anti-microsomal antibodies were positive in 3 patients (patients 1, 3, and 4). All patients had a very mild decrease of CD3 T-cell number, and 1 patient (patient 3) had a mild decrease of T-cell responses to mito-
gens, but none of our 5 patients had normal-range CD8 cell numbers. All patients were shown to have a deletion 22q11.2 detected by fluorescence in situ hybridization analysis with N25 (D22S75) or TUPLE1 probes.
DISCUSSION We report on 5 patients with the 22q11.2 deletion syndrome, confirmed by fluorescence in situ hybridization analysis, who were found to have Graves’ disease. Patients 1, 3, and 5 clearly had Graves’ disease by the laboratory results, but the diagnosis of Graves’ disease in patient 4 was tentative because of a mild increase in thyroid hormone level and a lack of TSH-receptor antibodies. It is noteworthy that all the patients had mild thrombocytopenia, and 2 of the 5 patients showed elevated anti-platelet antibodies (platelet-associated–immunoglobulin G). Patient 5 had an unusual clinical presentation because of the very early age at onset and atypical initial symptoms. Clinicians should be aware of the possibility of Graves disease in patients with a 22q11 deletion at any age. Autoimmune disorders have been described in patients with DiGeorge syndrome/veleocardiofacial syndrome. A single case report of a 13-year-old patient given the clinical diagnosis of DiGeorge syndrome has been reported to have an autoimmune thyroiditis (Graves’ disease).5 The karyotype of this patient was reported to be mosaicism for a deletion of chromosome 22q, although fluorescence in situ hybridization analysis was not available at that time. Recently Kawamura et al6 reported an 18-year-old female patient with partial DiGeorge syndrome and Graves’ disease. This patient was shown to have a deletion of 22q11.2 by fluorescence in situ hybridization analysis.6 Furthermore autoimmune hemolytic anemia,7,8 immune thrombocytopenia,7,9 recurrent immune cytopenia,8 and juvenile rheumatoid arthritis or polyarthritis
KAWAME ET AL
THE JOURNAL OF PEDIATRICS
VOLUME 139, NUMBER 6 have been described in patients with a 22q11.2 deletion.10 Our cases, along with previously described patients, lead us to suggest that this syndrome is associated with a predisposition to autoimmune disorders. The mechanism of predisposition to autoimmune diseases in the 22q11.2 deletion syndrome remains unknown. Several candidate genes, including the TSH receptor gene for nonautoimmune hyperthyroidism, that have been associated with Graves’ disease are reported, 3 but none of those genes is located in the chromosome 22q11 region. The literature has suggested that the defect of T-cell function might predispose to immune dysregulation and autoimmune diseases.11 We speculate that impaired T-cell differentiation or T-cell regulatory dysfunction may lead to the development of autoimmune diseases regardless of clinical immunodeficiency, documented T-cell dysfunction, or both. Although we did not perform human leukocyte antigen typing as a risk factor for Graves’ disease, Sullivan et al10 did confirm predisposing human leukocyte antigen types in her patients with juvenile rheumatoid arthritis and the 22q11.2 deletion. In addition, it has been shown that other genetic susceptibilities may contribute to the development of autoimmune diseases. We hypothesize that the combination of T-cell dysfunction, genetic susceptibilities, and appropriate environmental triggers can precipitate autoimmune disease in some patients with a 22q11.2 deletion syndrome. Consequently, autoimmune diseases overall are uncommon manifestations of the syndrome. We propose that the association between the 22q11.2 deletion and the de-
velopment of Graves’ disease is not a coincidence. First, the incidence of Graves’ disease in the general population has been estimated to be 17.7 in 100,000.12 Because 1 in 352 patients with the 22q11.2 deletion syndrome evaluated at The Children’s Hospital, Philadelphia, had Graves’ disease, the incidence of Graves’ disease in this population was approximately 16 times that seen in the general population. Second, patient 5 showed a very unusual presentation in terms of age at onset of Graves’ disease. Graves’ disease in children younger than 4 years is very rare. Finally, Graves’ disease, including autoimmune thyroid disease, is much less frequent in males; however, one of our patients was a male. Based on our findings, we suggest that Graves’ disease is an uncommon but significant manifestation of the 22q11.2 deletion syndrome. Evaluation of thyroid hormone function is indicated in patients with the syndrome and suggestive features of hyperthyroidism. Our observation and the literature are consistent with the theory that the 22q11.2 microdeletion syndrome is associated with a predisposition to autoimmune disorders, which contributes to the extremely variable phenotypes of affected patients.
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3. Zimmerman D, Lteif AN. Thyrotoxicosis in children. Endocrinol Metab Clin North Am 1998;27:109-25. 4. Adachi M, Tachibana K, Masuno M, Makita Y, Maesaka H, Okada T, et al. Clinical characteristics of children with hypoparathyroidism due to 22q11.2 microdeletion. Eur J Pediatr 1998;157:34-8. 5. Ham Pong AJ, Cavallo A, Holman GH, Goldman AS. DiGeorge syndrome: long-term survival complicated by Graves’ disease. J Pediatr 1985;106: 619-20. 6. Kawamura T, Nimura I, Hanafusa M, Fujikawa R, Okubo M, Egusa G, et al. DiGeorge syndrome with Graves’ disease: a case report. Endocr J 2000; 47:91-5. 7. Pinchas-Hamiel O, Mandel M, Engelberg S, Passwell JH. Immune hemolytic anemia, thrombocytopenia and liver disease in patient with DiGeorge syndrome. Isr J Med Sci 1994;30:530-2. 8. DePiero AD, Lourie EM, Berman BW, Robin NH, Zinn AB, Hostoffer RW. Recurrent immune cytopenias in two patients with DiGeorge/velocardiofacial syndrome. J Pediatr 1997;131:484-6. 9. Levy A, Michel G, Lemerrer M, Philip A. Idiopathic thrombocytopenia purpura in two mothers of children with DiGeorge sequence: a new component manifestation of deletion 22q11? Am J Med Genet 1997;69:356-9. 10. Sullivan KE, McDonald-McGinn DM, Driscoll DA, Zmijewski CM, Ellabban AS, Reed L, et al. Juvenile rheumatoid arthritis-like polyarthritis in chromosome 22q11.2 deletion syndrome (DiGeorge anomaly/velocardiofacial syndrome/ conotruncal anomaly face syndrome). Arthritis Rheum 1997;40:430-6. 11. Etzioni A, Pollack S. Autoimmune phenomena in DiGeorge Syndrome. Isr J Med Sci 1994;30:853. 12. Berglund J, Christensen SB, Hallengren B. Total and age-specific incidence of Graves’ thyrotoxicosis, toxic nodular goiter and solitary toxic adenoma in Malmo 1970-74. J Intern Med 1990; 227:137-41.
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