J Pediatr Endocr Met 2014; aop
Patient Report Federica De Corti*, Carlo Crivellaro, Giovanni Franco Zanon and Claudia Luzzatto
Consumptive hypothyroidism associated with parotid infantile hemangioma Abstract: Consumptive hypothyroidism is a rare condition usually described in association with diffuse infantile hemangioma of the liver, over-expressing type 3 iodothyronine-deiodinase. We report a case of acquired hypothyroidism associated with a parotid hemangioma in a male child, who was initially evaluated at 48 days of age due to persistent jaundice. Replacement hormonal therapy was promptly started, but resolution of the clinical and laboratory findings of hypothyroidism was only achieved at 3 months of age, when propranolol treatment was added to the therapeutic regimen. Our review of the literature retrieved only one case of proven consumptive hypothyroidism associated with a parotid infantile hemangioma, making a real incidence an underestimate: we believe one should consider this association a real possibility. Keywords: consumptive hypothyroidism; infantile hemangioma; parotid hemangioma; propranolol.
patients with diffuse HH and in 21.4% of patients with multifocal HH (3). Consumptive hypothyroidism in children with HH is due to overexpression of type 3 iodothyronine-deiodinase (D3) by the vascular tumor. This enzyme transforms thyroxine and triiodothyronine by deiodination into their inactive metabolites: reverse triiodothyronine and diiodothyronine, respectively (1). In recent years, beta-blockers have become one of the main treatments for troublesome life- or function-threatening or aesthetically disfiguring infantile hemangiomas (IH). Propranolol has demonstrated its effectiveness for treatment of diffuse HH, inducing regression of the hemangioma, and prompt resolution of hypothyroidism has been noted in several reports (4), as well as in our own clinical experience. This is the second description of IH of the parotid gland associated with consumptive hypothyroidism. It is noteworthy, not only for its rarity, but also for its favorable response to treatment with oral propranolol.
DOI 10.1515/jpem-2013-0420 Received October 25, 2013; accepted July 17, 2014
Clinical case Introduction The association of hypothyroidism and hepatic hemangioma (HH), first described by Huang et al. in 2000 (1), is now reported with increasing frequency (2). Kulungowski et al. collected a large series of HH in their register: they found that hypothyroidism was documented in 100% of
*Corresponding author: Federica De Corti, Unità Operativa di Chirurgia Pediatrica, Dipartimento della Salute della Donna e del Bambino, Azienda Ospedaliera Università di Padova, Via Nicolò Giustiniani 3, 35128 Padova, Italy, E-mail: [email protected] Federica De Corti, Giovanni Franco Zanon and Claudia Luzzatto: Pediatric Surgery Division, Department for the Health of Woman and Child, University-Hospital of Padova, Padua, Italy Carlo Crivellaro: Pediatric Unit, Hospital of Chioggia, Chioggia, Italy
A male child, born 2 weeks before term and after an uneventful pregnancy, weighed 3.560 kg at birth and presented with physiological jaundice (total serum bilirubin: 13 mg/dL). His physical examination was otherwise unremarkable, and he was discharged from the hospital on the fourth day of life, without any treatment. His routine neonatal screening was normal and ruled out congenital hypothyroidism. The infant returned to the Hospital of Chioggia, where he was born, at the age of 48 days because of persistent jaundice. The total and unconjugated bilirubin serum levels were mildly elevated (6 mg/dL and 2.29 mg/dL, respectively). The child was lethargic and had a typical face with swollen eyelids and tongue protrusion (Figure 1A). The serum thyrotropin (TSH) concentration was 8.28 mUI/mL (normal range 0.25–5 mUI/mL), and the serum thyroxin (FT4) concentration was 0.93 ng/dL
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2 De Corti et al.: Hypothyroidism associated with parotid IH
A
B
Figure 1 The patient before (A) and after (B) the treatment of hypothyroidism.
(normal range 0.7–1.7 ng/dL). Ultrasound examination of the thyroid gland was normal, and the search for antithyroid antibodies was negative. A swelling of the right cheek was noticed; however, it was attributed by the parents to a recent insect bite. Replacement treatment with levothyroxine was promptly started at the dosage of 2 μg/kg/day, with only a temporary normalization of TSH levels, soon followed by a recurrent increase (Figure 2 ). Levothyroxine therapy was adjusted up to 3 μg/kg/day. Parotid infantile hemangioma, measuring 4 cm in diameter, was diagnosed when the child was 3 months old. Further investigations by ultrasound and MRI scans were done because the right cheek swelling was progressive. There was no skin involvement. A complete assessment of the child, including liver ultrasound, did not demonstrate any other IH. The child was referred to the Pediatric Surgery Division of the University-Hospital of Padova, where he was admitted for a short time and then followed up monthly in the outpatient clinic. The electrocardiogram and echocardiogram demonstrated a normal heart function, and treatment with propranolol was begun in doses of 0.5 mg/kg/day divided into three doses (every
8 h), increasing to 1 mg/kg/day in the first week and up to 2 mg/kg/day in the second week and continued up to 18 months of age. Propranolol therapy not only caused progressive resolution of the parotid swelling but also a rapid and remarkable change in the child’s expression and behavior (Figure 1B). Ultrasound scan, performed at 11 months of age, confirmed complete regression of the IH. Levothyroxine was decreased to 2 μg/kg/day and maintained at this dosage, without adjustment for body weight, until 15 months of age. Propranolol was continued at the same dosage of 2 mg/kg/day until 9 months of age, and then it was very slowly tapered and stopped at 18 months of age. The child is now 2 years old and healthy, with no sign of recurrence or any cognitive delay.
Discussion Huang performed a retrospective review: among 92 patients with IH, 9 (10%) had serum thyrotropin levels high for age. In three cases the concentration was more than twice
TSH and FT4 LT
12
TSH, mU/mL 10
FT4, ng/dL P
8 6 4 2 0 55
70
76
91
104
119
147
174
201
262
685
Days of life
Figure 2 The evolution of values of thyrotropin (TSH) and of thyroxine (FT4) through time, following the introduction in therapy of levothyroxine (LT) and of propranolol (P).
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De Corti et al.: Hypothyroidism associated with parotid IH 3
the upper level of the normal range, and two of them had normal results on thyroid screening as newborns and were considered to have acquired hypothyroidism associated to their massive hepatic HH. Moreover, he assayed D3 activity of IH in five other patients and found that the activity of this hormone was increased in three of them (1). In our search of the literature we found only one case of proven consumptive hypothyroidism associated with a parotid IH as well. The child, whose thyroid gland was hypoplastic, failed to obtain the normalization of the serum thyrotropin levels with both replacement hormone and steroid therapy but showed an improvement of the hypothyroidism after starting propranolol (5). We were not aware of this report when we began treating our case, and no dosage of D3 was obtained. Despite lacking the laboratory proof of an increase of the enzyme concentration, we consider consumptive hypothyroidism as the most likely diagnosis, because congenital and autoimmune hypothyroidism were excluded and there was a clear temporal relationship between propranolol administration and clinical and laboratory improvement. Thyroid replacement therapy in consumptive hypothyroidism may require high dosage because the given hormone is inactivated by D3 as the native one. Compared to the other reported case, the child we treated required a relatively low dosage of levothyroxine to obtain the normalization of the hematic parameters. It is important to note that the other reported case had a thyroid hypoplasia, affecting its normal function. Regression of the hemangioma is the most important factor in achieving normalization of the thyroid function (5). In our case, the medical treatment was administered perhaps longer than actually needed as we were worried about a possible recurrence of symptoms. In fact, IH tends to grow again after suspension of propranolol in about 10% of cases (6, 7). We had a previous experience of recurrence of two parotid hemangiomas, which were successfully treated with propranolol until 12 months of age and recurred, one a few weeks after and the other one 3 months later. After these two episodes, we prefer to wean off the child of treatment gradually, instead of withdrawing therapy abruptly, thus prolonging treatment for a couple of months after the first year of age, generally considered as the final growing phase. Thyroid hormones are essential for neurodevelopment, for maintenance of the basal metabolic rate, and
for adaptive response to stress. Untreated hypothyroidism during the first year of life leads to severe cognitive impairment. This case suggests that not only HH, but also parotid IH, may cause consumptive hypothyroidism, probably overproducing D3. Therefore, we suggest a high degree of suspicion in all children with a large parotid IH, so that the appropriate substitutive treatment can be started before irreversible cerebral damage occurs. Not all parotid IH need to be treated. In a 100-case series from a big referral center, 70 required drug treatment because of deformity, ulceration, obstruction of the external auditory canal, narrowing of the subglottic space, or heart failure (8). Prevention of neurodevelopmental damage due to consumptive hypothyroidism should be added to this list as a strong indication for treatment. Conflict of interest statement: The authors declare that they have no conflict of interest.
References 1. Huang SA, Tu HM, Harney JW, Venihaki M, Butte AJ, et al. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med 2000;343:185–9. 2. Jassam N, Visser TJ, Brisco T, Bathia D, McClean P, et al. Consumptive hypothyroidism: a case report and review of the literature. Ann Clin Biochem 2011;48:186–9. 3. Kulungowski AM, Alomari AI, Chawla A, Christison-Lagay ER, Fishman SJ. Lessons from a liver hemangioma registry: subtype classification. J Pediatr Surg 2012;47:165–70. 4. Marsciani A, Alaggio R, Brisigotti M, Vergine G. Massive response of severe infantile hepatic emangioma to propranolol. Pediatr Blood Cancer 2010;54:176. 5. Vigone MC, Cortinovis F, Rabbiosi S, Di Frenna M, Passoni A, et al. Difficult treatment of consumptive hypothyroidism in a child with massive parotid hemangioma. J Pediatr Endocrinol Metab 2012;25:153–5. 6. Shehata N, Powell J, Dubois J, Hatami A, Rousseau E, et al. Late rebound of infantile hemangioma after cessation of oral propranolol. Pediatr Dermatol 2013;30:587–91. 7. Menezes MD, McCarter R, Greene EA, Bauman NM. Status of propranolol for treatment of infantile hemangioma and description of a randomized clinical trial. Ann Otol Rhinol Laryngol 2011;120:686–95. 8. Greene AK, Rogers GF, Mulliken JB. Management of parotid hemangioma in 100 children. Plast Reconstr Surg 2004;113: 53–60.
Brought to you by | University of Louisville Authenticated Download Date | 1/29/15 6:14 PM
Patient Report Federica De Corti*, Carlo Crivellaro, Giovanni Franco Zanon and Claudia Luzzatto
Consumptive hypothyroidism associated with parotid infantile hemangioma Abstract: Consumptive hypothyroidism is a rare condition usually described in association with diffuse infantile hemangioma of the liver, over-expressing type 3 iodothyronine-deiodinase. We report a case of acquired hypothyroidism associated with a parotid hemangioma in a male child, who was initially evaluated at 48 days of age due to persistent jaundice. Replacement hormonal therapy was promptly started, but resolution of the clinical and laboratory findings of hypothyroidism was only achieved at 3 months of age, when propranolol treatment was added to the therapeutic regimen. Our review of the literature retrieved only one case of proven consumptive hypothyroidism associated with a parotid infantile hemangioma, making a real incidence an underestimate: we believe one should consider this association a real possibility. Keywords: consumptive hypothyroidism; infantile hemangioma; parotid hemangioma; propranolol.
patients with diffuse HH and in 21.4% of patients with multifocal HH (3). Consumptive hypothyroidism in children with HH is due to overexpression of type 3 iodothyronine-deiodinase (D3) by the vascular tumor. This enzyme transforms thyroxine and triiodothyronine by deiodination into their inactive metabolites: reverse triiodothyronine and diiodothyronine, respectively (1). In recent years, beta-blockers have become one of the main treatments for troublesome life- or function-threatening or aesthetically disfiguring infantile hemangiomas (IH). Propranolol has demonstrated its effectiveness for treatment of diffuse HH, inducing regression of the hemangioma, and prompt resolution of hypothyroidism has been noted in several reports (4), as well as in our own clinical experience. This is the second description of IH of the parotid gland associated with consumptive hypothyroidism. It is noteworthy, not only for its rarity, but also for its favorable response to treatment with oral propranolol.
DOI 10.1515/jpem-2013-0420 Received October 25, 2013; accepted July 17, 2014
Clinical case Introduction The association of hypothyroidism and hepatic hemangioma (HH), first described by Huang et al. in 2000 (1), is now reported with increasing frequency (2). Kulungowski et al. collected a large series of HH in their register: they found that hypothyroidism was documented in 100% of
*Corresponding author: Federica De Corti, Unità Operativa di Chirurgia Pediatrica, Dipartimento della Salute della Donna e del Bambino, Azienda Ospedaliera Università di Padova, Via Nicolò Giustiniani 3, 35128 Padova, Italy, E-mail: [email protected] Federica De Corti, Giovanni Franco Zanon and Claudia Luzzatto: Pediatric Surgery Division, Department for the Health of Woman and Child, University-Hospital of Padova, Padua, Italy Carlo Crivellaro: Pediatric Unit, Hospital of Chioggia, Chioggia, Italy
A male child, born 2 weeks before term and after an uneventful pregnancy, weighed 3.560 kg at birth and presented with physiological jaundice (total serum bilirubin: 13 mg/dL). His physical examination was otherwise unremarkable, and he was discharged from the hospital on the fourth day of life, without any treatment. His routine neonatal screening was normal and ruled out congenital hypothyroidism. The infant returned to the Hospital of Chioggia, where he was born, at the age of 48 days because of persistent jaundice. The total and unconjugated bilirubin serum levels were mildly elevated (6 mg/dL and 2.29 mg/dL, respectively). The child was lethargic and had a typical face with swollen eyelids and tongue protrusion (Figure 1A). The serum thyrotropin (TSH) concentration was 8.28 mUI/mL (normal range 0.25–5 mUI/mL), and the serum thyroxin (FT4) concentration was 0.93 ng/dL
Brought to you by | University of Louisville Authenticated Download Date | 1/29/15 6:14 PM
2 De Corti et al.: Hypothyroidism associated with parotid IH
A
B
Figure 1 The patient before (A) and after (B) the treatment of hypothyroidism.
(normal range 0.7–1.7 ng/dL). Ultrasound examination of the thyroid gland was normal, and the search for antithyroid antibodies was negative. A swelling of the right cheek was noticed; however, it was attributed by the parents to a recent insect bite. Replacement treatment with levothyroxine was promptly started at the dosage of 2 μg/kg/day, with only a temporary normalization of TSH levels, soon followed by a recurrent increase (Figure 2 ). Levothyroxine therapy was adjusted up to 3 μg/kg/day. Parotid infantile hemangioma, measuring 4 cm in diameter, was diagnosed when the child was 3 months old. Further investigations by ultrasound and MRI scans were done because the right cheek swelling was progressive. There was no skin involvement. A complete assessment of the child, including liver ultrasound, did not demonstrate any other IH. The child was referred to the Pediatric Surgery Division of the University-Hospital of Padova, where he was admitted for a short time and then followed up monthly in the outpatient clinic. The electrocardiogram and echocardiogram demonstrated a normal heart function, and treatment with propranolol was begun in doses of 0.5 mg/kg/day divided into three doses (every
8 h), increasing to 1 mg/kg/day in the first week and up to 2 mg/kg/day in the second week and continued up to 18 months of age. Propranolol therapy not only caused progressive resolution of the parotid swelling but also a rapid and remarkable change in the child’s expression and behavior (Figure 1B). Ultrasound scan, performed at 11 months of age, confirmed complete regression of the IH. Levothyroxine was decreased to 2 μg/kg/day and maintained at this dosage, without adjustment for body weight, until 15 months of age. Propranolol was continued at the same dosage of 2 mg/kg/day until 9 months of age, and then it was very slowly tapered and stopped at 18 months of age. The child is now 2 years old and healthy, with no sign of recurrence or any cognitive delay.
Discussion Huang performed a retrospective review: among 92 patients with IH, 9 (10%) had serum thyrotropin levels high for age. In three cases the concentration was more than twice
TSH and FT4 LT
12
TSH, mU/mL 10
FT4, ng/dL P
8 6 4 2 0 55
70
76
91
104
119
147
174
201
262
685
Days of life
Figure 2 The evolution of values of thyrotropin (TSH) and of thyroxine (FT4) through time, following the introduction in therapy of levothyroxine (LT) and of propranolol (P).
Brought to you by | University of Louisville Authenticated Download Date | 1/29/15 6:14 PM
De Corti et al.: Hypothyroidism associated with parotid IH 3
the upper level of the normal range, and two of them had normal results on thyroid screening as newborns and were considered to have acquired hypothyroidism associated to their massive hepatic HH. Moreover, he assayed D3 activity of IH in five other patients and found that the activity of this hormone was increased in three of them (1). In our search of the literature we found only one case of proven consumptive hypothyroidism associated with a parotid IH as well. The child, whose thyroid gland was hypoplastic, failed to obtain the normalization of the serum thyrotropin levels with both replacement hormone and steroid therapy but showed an improvement of the hypothyroidism after starting propranolol (5). We were not aware of this report when we began treating our case, and no dosage of D3 was obtained. Despite lacking the laboratory proof of an increase of the enzyme concentration, we consider consumptive hypothyroidism as the most likely diagnosis, because congenital and autoimmune hypothyroidism were excluded and there was a clear temporal relationship between propranolol administration and clinical and laboratory improvement. Thyroid replacement therapy in consumptive hypothyroidism may require high dosage because the given hormone is inactivated by D3 as the native one. Compared to the other reported case, the child we treated required a relatively low dosage of levothyroxine to obtain the normalization of the hematic parameters. It is important to note that the other reported case had a thyroid hypoplasia, affecting its normal function. Regression of the hemangioma is the most important factor in achieving normalization of the thyroid function (5). In our case, the medical treatment was administered perhaps longer than actually needed as we were worried about a possible recurrence of symptoms. In fact, IH tends to grow again after suspension of propranolol in about 10% of cases (6, 7). We had a previous experience of recurrence of two parotid hemangiomas, which were successfully treated with propranolol until 12 months of age and recurred, one a few weeks after and the other one 3 months later. After these two episodes, we prefer to wean off the child of treatment gradually, instead of withdrawing therapy abruptly, thus prolonging treatment for a couple of months after the first year of age, generally considered as the final growing phase. Thyroid hormones are essential for neurodevelopment, for maintenance of the basal metabolic rate, and
for adaptive response to stress. Untreated hypothyroidism during the first year of life leads to severe cognitive impairment. This case suggests that not only HH, but also parotid IH, may cause consumptive hypothyroidism, probably overproducing D3. Therefore, we suggest a high degree of suspicion in all children with a large parotid IH, so that the appropriate substitutive treatment can be started before irreversible cerebral damage occurs. Not all parotid IH need to be treated. In a 100-case series from a big referral center, 70 required drug treatment because of deformity, ulceration, obstruction of the external auditory canal, narrowing of the subglottic space, or heart failure (8). Prevention of neurodevelopmental damage due to consumptive hypothyroidism should be added to this list as a strong indication for treatment. Conflict of interest statement: The authors declare that they have no conflict of interest.
References 1. Huang SA, Tu HM, Harney JW, Venihaki M, Butte AJ, et al. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med 2000;343:185–9. 2. Jassam N, Visser TJ, Brisco T, Bathia D, McClean P, et al. Consumptive hypothyroidism: a case report and review of the literature. Ann Clin Biochem 2011;48:186–9. 3. Kulungowski AM, Alomari AI, Chawla A, Christison-Lagay ER, Fishman SJ. Lessons from a liver hemangioma registry: subtype classification. J Pediatr Surg 2012;47:165–70. 4. Marsciani A, Alaggio R, Brisigotti M, Vergine G. Massive response of severe infantile hepatic emangioma to propranolol. Pediatr Blood Cancer 2010;54:176. 5. Vigone MC, Cortinovis F, Rabbiosi S, Di Frenna M, Passoni A, et al. Difficult treatment of consumptive hypothyroidism in a child with massive parotid hemangioma. J Pediatr Endocrinol Metab 2012;25:153–5. 6. Shehata N, Powell J, Dubois J, Hatami A, Rousseau E, et al. Late rebound of infantile hemangioma after cessation of oral propranolol. Pediatr Dermatol 2013;30:587–91. 7. Menezes MD, McCarter R, Greene EA, Bauman NM. Status of propranolol for treatment of infantile hemangioma and description of a randomized clinical trial. Ann Otol Rhinol Laryngol 2011;120:686–95. 8. Greene AK, Rogers GF, Mulliken JB. Management of parotid hemangioma in 100 children. Plast Reconstr Surg 2004;113: 53–60.
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