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Acquired hypothyroidism in a very young infant with Omenn’s syndrome
CLINICAL AND LABORATORY OBSERVATIONS i¸
hypothyroidism in a very young infant with yndrome Yukikazu Kaino, ~ID, ~odbiko O t o b , .4lID,Kiriko TokuOa, ftID, Hiroki HiraL mD, Takuo Ito, MD, and Kaicbi Kh?a, MD, PbD
A very young male infant with Omenn's syndrome had acquired hypothyroidism that was most likely caused by autoimmune thyroiditis. The hypothyroidism appeared at 3 months of age. These 2 rare conditions have not previously been reported occurring together. This case suggests that autoimmune thyroiditis may be another abnormal finding in Omenn's syndrome. (J Pediatr 2000; 136:111-3)
Omenn's syndrome is a rare inherited immunodeficiency disorder of infancy, characterized by a diffuse, erythematous, scaly rash; recurrent infection; protracted diarrhea; lymphadenopathy; hepatosplenomegaly; peripheral blood lymphocytosis and eosinophilia; and lymphocytic infiltration in the skin, gut, liver, and spleen. Since the syndrome was first described in 1965 by Omenn, 1 other cases have been reported, broadening the spectrum of its clinical manifestations and immunologic abnormalities. 2-7 In young children, acquired hypothyroidism is usually seen after 3 Ftvm the Department of Pedhzlriea, Ehime Uniuersily Sct,ool ofMedicine, Ebime, Japan.
Submitted for publication Mar 18, 1999; revision received July 7, 1999; accepted Aug 11, 1999. Reprint requests: Yukikazu Kaino, MD, Department of Pediatrics, Ehime University School of Medicine, Shigenobu, Ehime 7910295, Japan. Copyright © 2000 by Mosby, Inc. 0022-3476/2000/$12.00 + 0 9/22/102372
years of age, and its most common cause is autoimmune thyroiditis. The development of acquired hypothyroidism in infants younger than 1 year of age is very rare, and the clinical features are usually complex. 8-1I We describe here a very young infant with Omenn's syndrome and acquired hypothyroidism that was most likely caused by autoimmune thyroiditis. This case suggests that in Omenn's syndrome, functionally abnormal lymphocytes may infiltrate the thyroid gland, as well as the skin and gut, and cause thyroid destruction in early infancy.
CASE REPORT This boy was the first child of nonconsanguineous parents. There was no family history of early death in infancy, thyroid or other endocrine disorders, or immunodeficiency. The pregnancy and delivery were uneventful. The results of neonatal thyroid screening were normal. He first developed fever,
diarrhea, and skin lesions between 1 and 2 months of age. His growth and development slowed, and at 2 months of age, he was admitted to other hospitals twice because of fever and diarrhea. He never received a transfusion. On the 84th day of life, he was referred to our hospital for further evaluation of recurrent infection, protracted diarrhea, and failure to thrive. On admission, his general condition was poor, and he had diffuse exfoliative erythroderma and alopecia. The thyroid gland was not palpable. He was treated with intravenous immunoglobulin and antibiotics. Two weeks later, lymphadenopathy, hepatosplenomegaly, peripheral blood lymphocytosis, and eosinophilia appeared. After 3 weeks, he underwent surgery for occlusive ileus. A thickening of the ileocecal valve and the intestine around the terminal portion of the ileum was found. Lymph node and skin biopsies were performed during the operation. One month after admission, generalized lymphadenopathy and hepatosplenomegaly became more prominent. Laboratory investigations showed leukocytosis with marked lymphocytosis and eosinophilia (Table I), decreased levels of all serum immunoglobulins, and no maternal chimerism in HLA typing or chromosome analysis. Surface marker analysis of the blood and lymph node lymphocytes revealed a marked III
KAINO ET AL
THE JOURNAL OF PEDIATRICS
JANUARY2000 Table I. Hematologic and biochemical investigations
Table II. Immunofluorescence analysisof the lymphocyte populations in the periph-
eral blood and lymph nodes
predominance of T cells, T-cell oligoclonality, and a high proportion of T cells with activation antigens (Table II). In addition, specimens of the skin, gut, lymph nodes, and bone marrow exhib112
ited characteristic histopathologic findings. On the basis of these findings, we made a diagnosis of Omenn's syndrome. At 124 days of age, immunosuppressive therapy with prednisolone and
cyclosporine was initiated to treat the clinical and immunologic abnormalities associated with Omenn's syndrome. Before that, thyroid function tests were carried out, although there were very few symptoms and signs of thyroid hormone deficiency. To our surprise, the thyroid data revealed severe biochemical hypothyroidism (Table I). The serum thyroglobulin level was markedly elevated. A low titer (hl00) of anti-thyroid microsome antibodies and a low level (1.4 U/mL) of anti-thyroid peroxidase antibodies (negative <0.3) were detected by hemagglutination and radioimmunoassay, respectively. Results of a technetium thyroid scan were normal. Bone age was not delayed. Both parents were euthyroid without anti-thyroid antibodies. Substitution therapy with L-thyroxine (9 gg/kg/d) was initiated immediately after diagnosis of hypothyroidism, and from then on, thyroid function was monitored at periodic intervals. Thyroid function before diagnosis of hypothyroidism was investigated by using stored sera. The investigations revealed that the hypothyroidism with an increased level of serum thyroglobulin had appeared soon after admission and worsened rapidly and also that thyroid function had deteriorated with the worsening of leukocytosis, lymphocytosis, and hypereosinophilia associated with Omenn's syndrome.
THE JOURNAL OF PEDIATRICS VOLUNE 136, NUMBER I
On the 24th day of L-thyroxine therapy, thyroid-stimulating hormone, free thyroxine, and free triiodothyronine levels returned to normal. Two months after initiation of immunosuppressive and L-thyroxine therapy, a slight improvement in growth failure, skin lesions, and l~nphadenopathy was seen; and the thyroglobulin level decreased to normal. A thyroid biopsy was performed 41A months after initiation of the therapy after informed consent had been obtained from his parents. The patient is 10 months old at the time of writing. He is receiving L-thyroxine therapy (5 ~tg/kg/d). Serum thyroglobulin levels are sometimes slightly elevated.
DISCUSSION The clinical, laboratory, and pathologic findings in this child are in full accord with those of reported cases of Omenn's syndrome, except for the serum IgE level. His serum immunoglobulin levels were all ve W low. In this syndrome, IgE levels are usually reported to be elevated. 2-4'6 However, this syndrome has been shown to be heterogeneous and to have a wide spectrum of immunologic abnormalities. Cases of Omenn's syndrome
KAINO ET AL
without elevated IgE have also been reported. 4,6 Hypothyroidism discovered in early infancy usually results from an undetected case of congenital hypothyroidism. In this child, however, we believe that the hypothyroidism was acquired and was caused by autoimmune thyroiditis. In this case, thyroid antibodies were detected, despite hypogammaglobulinemia. However, the positive results may be unreliable, because he was treated with exogenous intravenous immunoglobulin. This idea is supported by the thyroid histopathologic findings, showing the presence of lymphocyte infiltration. Its severity was mild compared with that in the skin or gut tissue obtained before immunosuppressive therapy. At the time of the thyroid biopsy, the serum thyroglobulin level, which can represent the intensity of thyroid destruction, was within normal range. On histologic evaluation, regeneration of the thyroid tissue was also seen. The immunosuppressive therapy may have contributed to an inhibition of thyroid destruction. Acquired hypothyroidism caused by autoimmune thyroiditis in infants less than 1 year old is extremely rare, and its clinical picture is different from that in later childhood. 8-1I It has been reported in 3 infants who also developed other conditions. 9-11 These patients with hypothyroidism and high thyroid antibody titers had recurrent infection and died early. Our patient also has a serious clinical course because of Omenn's syndrome. We believe that the basic disorder underlying these cases is a primary immunodeficiency, which may be related to abnormalities in %ceil functions that cause vigorous thyroid destruction in such an early period of life. At present, Omenn's syndrome remains a mostly fatal disease. Bone marrow transplantation offers the only real therapeutic option. 6 Our patient is scheduled to undergo bone marrow transplantation at 11 months of age. In conclusion, it is conceivable that in this case there is a close relationship
between the 2 rare conditions. The hypothyroidism probably resulted from the immunologic abnormalities associated with Omenn's syndrome.
REFERENCES 1. Omenn GS. Familial reticuloendotheliosis with eosinophilia. N Engl J Med 1965;273:427-32. 2. Ochs HD, Davis SD, Mickelson E, Lerner KG, Wedgwood RJ. Combined immunodeficieney and reticuloendotheliosis with eosinophilia. J Pediatr 1974;85:463-5. 3. Businco L, Di Fazio A, Ziruolo MG, Boner AL, Valletta EA, Ruco LP, et al. Clinical and immunological findings in four infants with Omenn's syndrome: a form of severe combined immunodeficiencywith phenotypicallynormal T cells, elevated IgE, and eosinophilia. Clin Immunol Imrnunopatho11987;44:123-33. 4. Jouan H, Le Deist E NezelofC. Omenn's syndrome-pathologic arguments in favor of a graft versus host pathogenesis. Hum Patho11987;18:1101-8. 5. de Saint-Basile G, Le Deist F, de Villartay JP, Cerf-Bensussan N, Journet O, Brousse N, et al. Restricted heterogeneity of T lymphocytes in combined immunodeficieney with hypereosinophilia (Omenn's syndrome). J Clin Invest 1991;87:1352-9. 6. Gomez L, Le Deist E Blanche S, Cavazzana-Calvo M, Griscelli C, Fischer A. Treatment of Omenn syndrome by bone marrow transplantation. J Pediatr 1995;127:76-81. 7. Villa A, Santagata S, Bozzi E Giliani S, Frattini A, Imberti L, et al. Partial V(D)J recombination activity leads to Omenn syndrome. Cell 1998;95: 885-96. 8. Foley TP Jr, Abbassi V, Copeland KC, Draznin MB. Hypothyroidism caused by chronic autoimmune thyroiditis in very young infants. N Engl J Med 1994;330:466-8. 9. Powell BR, Buist NRM, Stenzel P. An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy. J Pediatr 1982;100:751-7. 10. Savage MO, Mirakian R, Wozniak ER, Jenkins HR, Malone M, Phillips AD, et al. Specific autoantibodies to gut epithelium in two infants with severe protracted diarrhoea. J Pediatr Gastroenterol Nutr 1985;4:187-95. 11. Ostergaard GZ, Jacobsen BB. Atrophic, autoimmune thyroiditis in infancy. Horm Res 1989;31:190-2. 1|3
hypothyroidism in a very young infant with yndrome Yukikazu Kaino, ~ID, ~odbiko O t o b , .4lID,Kiriko TokuOa, ftID, Hiroki HiraL mD, Takuo Ito, MD, and Kaicbi Kh?a, MD, PbD
A very young male infant with Omenn's syndrome had acquired hypothyroidism that was most likely caused by autoimmune thyroiditis. The hypothyroidism appeared at 3 months of age. These 2 rare conditions have not previously been reported occurring together. This case suggests that autoimmune thyroiditis may be another abnormal finding in Omenn's syndrome. (J Pediatr 2000; 136:111-3)
Omenn's syndrome is a rare inherited immunodeficiency disorder of infancy, characterized by a diffuse, erythematous, scaly rash; recurrent infection; protracted diarrhea; lymphadenopathy; hepatosplenomegaly; peripheral blood lymphocytosis and eosinophilia; and lymphocytic infiltration in the skin, gut, liver, and spleen. Since the syndrome was first described in 1965 by Omenn, 1 other cases have been reported, broadening the spectrum of its clinical manifestations and immunologic abnormalities. 2-7 In young children, acquired hypothyroidism is usually seen after 3 Ftvm the Department of Pedhzlriea, Ehime Uniuersily Sct,ool ofMedicine, Ebime, Japan.
Submitted for publication Mar 18, 1999; revision received July 7, 1999; accepted Aug 11, 1999. Reprint requests: Yukikazu Kaino, MD, Department of Pediatrics, Ehime University School of Medicine, Shigenobu, Ehime 7910295, Japan. Copyright © 2000 by Mosby, Inc. 0022-3476/2000/$12.00 + 0 9/22/102372
years of age, and its most common cause is autoimmune thyroiditis. The development of acquired hypothyroidism in infants younger than 1 year of age is very rare, and the clinical features are usually complex. 8-1I We describe here a very young infant with Omenn's syndrome and acquired hypothyroidism that was most likely caused by autoimmune thyroiditis. This case suggests that in Omenn's syndrome, functionally abnormal lymphocytes may infiltrate the thyroid gland, as well as the skin and gut, and cause thyroid destruction in early infancy.
CASE REPORT This boy was the first child of nonconsanguineous parents. There was no family history of early death in infancy, thyroid or other endocrine disorders, or immunodeficiency. The pregnancy and delivery were uneventful. The results of neonatal thyroid screening were normal. He first developed fever,
diarrhea, and skin lesions between 1 and 2 months of age. His growth and development slowed, and at 2 months of age, he was admitted to other hospitals twice because of fever and diarrhea. He never received a transfusion. On the 84th day of life, he was referred to our hospital for further evaluation of recurrent infection, protracted diarrhea, and failure to thrive. On admission, his general condition was poor, and he had diffuse exfoliative erythroderma and alopecia. The thyroid gland was not palpable. He was treated with intravenous immunoglobulin and antibiotics. Two weeks later, lymphadenopathy, hepatosplenomegaly, peripheral blood lymphocytosis, and eosinophilia appeared. After 3 weeks, he underwent surgery for occlusive ileus. A thickening of the ileocecal valve and the intestine around the terminal portion of the ileum was found. Lymph node and skin biopsies were performed during the operation. One month after admission, generalized lymphadenopathy and hepatosplenomegaly became more prominent. Laboratory investigations showed leukocytosis with marked lymphocytosis and eosinophilia (Table I), decreased levels of all serum immunoglobulins, and no maternal chimerism in HLA typing or chromosome analysis. Surface marker analysis of the blood and lymph node lymphocytes revealed a marked III
KAINO ET AL
THE JOURNAL OF PEDIATRICS
JANUARY2000 Table I. Hematologic and biochemical investigations
Table II. Immunofluorescence analysisof the lymphocyte populations in the periph-
eral blood and lymph nodes
predominance of T cells, T-cell oligoclonality, and a high proportion of T cells with activation antigens (Table II). In addition, specimens of the skin, gut, lymph nodes, and bone marrow exhib112
ited characteristic histopathologic findings. On the basis of these findings, we made a diagnosis of Omenn's syndrome. At 124 days of age, immunosuppressive therapy with prednisolone and
cyclosporine was initiated to treat the clinical and immunologic abnormalities associated with Omenn's syndrome. Before that, thyroid function tests were carried out, although there were very few symptoms and signs of thyroid hormone deficiency. To our surprise, the thyroid data revealed severe biochemical hypothyroidism (Table I). The serum thyroglobulin level was markedly elevated. A low titer (hl00) of anti-thyroid microsome antibodies and a low level (1.4 U/mL) of anti-thyroid peroxidase antibodies (negative <0.3) were detected by hemagglutination and radioimmunoassay, respectively. Results of a technetium thyroid scan were normal. Bone age was not delayed. Both parents were euthyroid without anti-thyroid antibodies. Substitution therapy with L-thyroxine (9 gg/kg/d) was initiated immediately after diagnosis of hypothyroidism, and from then on, thyroid function was monitored at periodic intervals. Thyroid function before diagnosis of hypothyroidism was investigated by using stored sera. The investigations revealed that the hypothyroidism with an increased level of serum thyroglobulin had appeared soon after admission and worsened rapidly and also that thyroid function had deteriorated with the worsening of leukocytosis, lymphocytosis, and hypereosinophilia associated with Omenn's syndrome.
THE JOURNAL OF PEDIATRICS VOLUNE 136, NUMBER I
On the 24th day of L-thyroxine therapy, thyroid-stimulating hormone, free thyroxine, and free triiodothyronine levels returned to normal. Two months after initiation of immunosuppressive and L-thyroxine therapy, a slight improvement in growth failure, skin lesions, and l~nphadenopathy was seen; and the thyroglobulin level decreased to normal. A thyroid biopsy was performed 41A months after initiation of the therapy after informed consent had been obtained from his parents. The patient is 10 months old at the time of writing. He is receiving L-thyroxine therapy (5 ~tg/kg/d). Serum thyroglobulin levels are sometimes slightly elevated.
DISCUSSION The clinical, laboratory, and pathologic findings in this child are in full accord with those of reported cases of Omenn's syndrome, except for the serum IgE level. His serum immunoglobulin levels were all ve W low. In this syndrome, IgE levels are usually reported to be elevated. 2-4'6 However, this syndrome has been shown to be heterogeneous and to have a wide spectrum of immunologic abnormalities. Cases of Omenn's syndrome
KAINO ET AL
without elevated IgE have also been reported. 4,6 Hypothyroidism discovered in early infancy usually results from an undetected case of congenital hypothyroidism. In this child, however, we believe that the hypothyroidism was acquired and was caused by autoimmune thyroiditis. In this case, thyroid antibodies were detected, despite hypogammaglobulinemia. However, the positive results may be unreliable, because he was treated with exogenous intravenous immunoglobulin. This idea is supported by the thyroid histopathologic findings, showing the presence of lymphocyte infiltration. Its severity was mild compared with that in the skin or gut tissue obtained before immunosuppressive therapy. At the time of the thyroid biopsy, the serum thyroglobulin level, which can represent the intensity of thyroid destruction, was within normal range. On histologic evaluation, regeneration of the thyroid tissue was also seen. The immunosuppressive therapy may have contributed to an inhibition of thyroid destruction. Acquired hypothyroidism caused by autoimmune thyroiditis in infants less than 1 year old is extremely rare, and its clinical picture is different from that in later childhood. 8-1I It has been reported in 3 infants who also developed other conditions. 9-11 These patients with hypothyroidism and high thyroid antibody titers had recurrent infection and died early. Our patient also has a serious clinical course because of Omenn's syndrome. We believe that the basic disorder underlying these cases is a primary immunodeficiency, which may be related to abnormalities in %ceil functions that cause vigorous thyroid destruction in such an early period of life. At present, Omenn's syndrome remains a mostly fatal disease. Bone marrow transplantation offers the only real therapeutic option. 6 Our patient is scheduled to undergo bone marrow transplantation at 11 months of age. In conclusion, it is conceivable that in this case there is a close relationship
between the 2 rare conditions. The hypothyroidism probably resulted from the immunologic abnormalities associated with Omenn's syndrome.
REFERENCES 1. Omenn GS. Familial reticuloendotheliosis with eosinophilia. N Engl J Med 1965;273:427-32. 2. Ochs HD, Davis SD, Mickelson E, Lerner KG, Wedgwood RJ. Combined immunodeficieney and reticuloendotheliosis with eosinophilia. J Pediatr 1974;85:463-5. 3. Businco L, Di Fazio A, Ziruolo MG, Boner AL, Valletta EA, Ruco LP, et al. Clinical and immunological findings in four infants with Omenn's syndrome: a form of severe combined immunodeficiencywith phenotypicallynormal T cells, elevated IgE, and eosinophilia. Clin Immunol Imrnunopatho11987;44:123-33. 4. Jouan H, Le Deist E NezelofC. Omenn's syndrome-pathologic arguments in favor of a graft versus host pathogenesis. Hum Patho11987;18:1101-8. 5. de Saint-Basile G, Le Deist F, de Villartay JP, Cerf-Bensussan N, Journet O, Brousse N, et al. Restricted heterogeneity of T lymphocytes in combined immunodeficieney with hypereosinophilia (Omenn's syndrome). J Clin Invest 1991;87:1352-9. 6. Gomez L, Le Deist E Blanche S, Cavazzana-Calvo M, Griscelli C, Fischer A. Treatment of Omenn syndrome by bone marrow transplantation. J Pediatr 1995;127:76-81. 7. Villa A, Santagata S, Bozzi E Giliani S, Frattini A, Imberti L, et al. Partial V(D)J recombination activity leads to Omenn syndrome. Cell 1998;95: 885-96. 8. Foley TP Jr, Abbassi V, Copeland KC, Draznin MB. Hypothyroidism caused by chronic autoimmune thyroiditis in very young infants. N Engl J Med 1994;330:466-8. 9. Powell BR, Buist NRM, Stenzel P. An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy. J Pediatr 1982;100:751-7. 10. Savage MO, Mirakian R, Wozniak ER, Jenkins HR, Malone M, Phillips AD, et al. Specific autoantibodies to gut epithelium in two infants with severe protracted diarrhoea. J Pediatr Gastroenterol Nutr 1985;4:187-95. 11. Ostergaard GZ, Jacobsen BB. Atrophic, autoimmune thyroiditis in infancy. Horm Res 1989;31:190-2. 1|3