THYROID Volume 2, Number
Mary
Ann
I,
1992
Liebert, Inc., Publishers
Dextrothyroxine in the Treatment of Generalized Thyroid Hormone Resistance in a Boy Homozygous for a Defect in the T3 Receptor I. DAVID SCHWARTZ and BARRY B. BERCU
ABSTRACT The dextroisomer of thyroxine (D-T4) has been shown to have suppressive effects on pituitary TSH secretion in euthyroid individuals and patients with mild thyroid hormone resistance. We treated a 3-year-old boy with D-T4 who was homozygous for a T3 receptor defect, resulting in a complex clinical picture of tissue-specific hyperthyroidism and hypothyroidism. There was no evidence of significant alteration in thyroid physiology, including serum concentrations of basal and TRH stimulated TSH or echocardiographic parameters measuring systolic time interval. We conclude that D-T4 at a daily dose of 6 mg (0.65 mg/kg) was ineffective in this*boy with homozygous dominant negative thyroid hormone resistance.
CASE REPORT
INTRODUCTION
Several reported (1-6) describing perhaps
resistance have three types of resistance
This kindred has been presented previously (6). The propositus the firstborn child to first cousins who both had mild GTHR. The pregnancy was complicated by fetal tachycardia and preterm labor at 35 weeks gestation, resulting in an unsupervised home delivery. The birth weight was 1480 g, length 41.5 cm. The neonatal course included tachycardia, respiratory distress, polycythemia, patent ductus arteriosus, hyperbilirubinemia, hypofibrinoginemia, a prominent stare, bicuspid valve insufficiency, right inguinal hernia, and left hydrocele. Goiter was not appreci¬ ated initially. A metabolic screen obtained at 3 days of age revealed T4 of 432 nmol/L (33.6 µg/dL) and TSH of 299 mU/L. I23I uptake and scan of the thyroid demonstrated increased uptake (50% at 24 h), with a moderately enlarged gland. The hemiskeletal bone age was less than term at 4 weeks of age. He had continued signs of thyrotoxicosis (tachycardia, poor weight gain, frequent stools) and hypothyroidism (developmental and skeletal maturation delay) and subsequently developed a large, smooth, soft goiter, noncommu-
kindreds with thyroid hormone
been states,
was
comprising a clinical spectrum: (a) generalized thyroid hormone resistance (GTHR), (b) selective pituitary thyroid hormone resistance (SPTHR), and (c) peripheral thyroid hormone resistance (PTHR) (3-8). Resistance to the metabolic effects of thyroxine (L-T4) may be tissue dependent (9). The dextroisomer of L-T4 (dextrothyroxine; D-T4) is metab¬ olized to D-T, (10) and reverse D-T,. The former binds to the T, receptor with 13% of the affinity of L-T, in vitro (11) and is metabolically less active than the levoisomer. We report our recent experience with D-T4 in treating a boy with evidence of homozygous (dominant negative) autosomal dominant thyroid hormone resistance due to a three base pair (bp) deletion in the c-erbA beta-thyroid hormone receptor gene resulting in the loss of threonine codon 332 (12) of the thyroid hormone receptor. Our objectives in treating this patient were to decrease the clinical manifestations of hyperthyroidism in order to optimize growth, caloric use, and neurologic development and to mini¬ mize the potential risk of pituitary hyperplasia.
Department of Pediatrics, Section Hospital. St. Petersburg, Florida. Presented in part
at
of
the International
Endocrinology. University
nicating hydrocephalus (requiring
a
intermittent seizures controlled with growth retardation.
of South Florida
College
Symposium on Advances in Perinatal Thyroidology, 15
of Medicine.
ventriculoperitoneal shunt), phénobarbital, and marked
Tampa,
December 2, 1990,
Florida, and All Children's
Longboat Key.
Florida.
16
SCHWARTZ AND BERCU
Assays and procedures
isomerie forms of T4 were unavailable. Therefore, TG concentrations were used as an index of thyroid function, since TG concentrations are positively correlated with thyroid hyperfunction (13). Serum concentrations of angiotensin-converting enzyme and sex hormone-binding globulin (data not shown) and TBG and cholesterol did not change signifi¬ cantly with D-T4 therapy. measure
serum
Serum concentrations of T4 and T, were measured by radio¬ 1987 to 1989. after which an enzymelinked assay was used. The hypothalamic-pituitary-thyroid axis was assessed with TRH (7 µg/kg i.V.). Serum concentrations of
immunoassay (RIA) from
thyroglobulin (TG), thyroxine-binding globulin (TBG), freeT4, and free T, were measured by Nichols Institute (San Juan Capistrano, CA). Free hormones were measured by equilibrium dialysis. Echocardiography was performed as an assessment of func¬ tional peripheral thyroid status first using a Toshiba 65 and later a Toshiba 140 system. The preejection period (PEP) was the period from the initiation of the Q wave on the simultaneous electrocardiogram to aortic valve opening. The left ventricular ejection time (LVET) was the time between opening and closure
DISCUSSION The therapeutic approach to patients with SPTHR is to decrease pituitary TSH secretion in order to decrease secretion of thyroid hormones and improve symptoms. Indirect methods to lower TSH secretion by modulating the T, receptor have met with variable success and include the use of exogenous L-T4 and L-T, and analogs to L-T,, including 3,5,3'-triiodothyroacetic acid (TRIAC) (4,14-16). Treatment may not be required in patients with mild GTHR. In those clinically mildly hypothyroid patients, these thyromimetic agents often result in clinical improvement and lowered serum concentration of TSH. Direct methods to decrease TSH secretion include somatostatin and dopaminergic analogs (4,17-19). Our patient showed no change in TSH secretion during acute somatostatin infusion (data not shown). Because of the extraordinary elevations in thyroid hormone concentrations, therapy with supplemental thyromi¬ metic agents did not seem to be warranted. Hamonetal. reported using D-T4 in treating a 15-month-old boy with mild SPTHR and accelerated height velocity and bone age advancement who failed a trial of TRIAC (20). There was clinical improvement, decreased serum TSH and L-T4 concentrations [4.6 to 1.8 mU/L and 230 to 93 nmol/L (18.0 to 7.3 µg/dL, stereospecific assay), respectively] and slowing of growth rate and degree of skeletal maturation after 16 months of D-T4 (Dynothel, 5 mg/day) (20). Dorcy et al., using low doses of D-T4 in three adults with mild SPTHR, described lessened symptoms of thyrotoxicosis and lowered TG as well as basal and peak TSH concentrations (21), although their patients received D-T4 concurrently with PTU
of the aortic valve.
Study approval was obtained from the institutional review boards of the University of South Florida College of Medicine and All Children's Hospital. Parents signed informed consent. The patient underwent two separate trials of D-T4. D-T4 first was provided as Choloxin, generously provided by The Boots Company (Shreveport, LA). In the second trial, D-T4 was
provided as Dynothel, generously provided by Henning (Berlin, Germany). During each trial, the patient was reassessed regu¬ larly, and the dosage of D-T4 was adjusted based on clinical response and biochemical parameters.
RESULTS The clinical and laboratory course before initiation of D-T4 is shown in Table 1. Normal feedback of the pituitary-thyroid axis was shown by marked lowering of T4 with concomitant eleva¬ tion in TSH while the child inadvertently received approxi¬ mately 10 times the prescribed dose of propylthiouracil (PTU) for 1 week. Parameters of thyroid physiology, including cardiac tissue sensitivity, during both D-T4 trials are shown in Table 2 and Figures 1 and 2. Methods to specifically differentiate and
Table 1. Biochemical
and
Treatment Course of Child with GTHR Before Therapy with
TSH
Age
T4
(mU/L)
(nmol/L)
3 days 25 days 1.5 months 2.3 months 4.3 months 9.5 months 11.5 months 19.5 months 33.5 months Normal range
299 389 670 395 290 198 160 155 102 0.5-5.0
432
653b 37 273 822 336 252 331
641" 94-194
D-T4
(nmol/L)
A"
20.7 1.0 15.3 17.6 17.3 9.1 12.4 15.3 1.6-4.1
Mary
Ann
I,
1992
Liebert, Inc., Publishers
Dextrothyroxine in the Treatment of Generalized Thyroid Hormone Resistance in a Boy Homozygous for a Defect in the T3 Receptor I. DAVID SCHWARTZ and BARRY B. BERCU
ABSTRACT The dextroisomer of thyroxine (D-T4) has been shown to have suppressive effects on pituitary TSH secretion in euthyroid individuals and patients with mild thyroid hormone resistance. We treated a 3-year-old boy with D-T4 who was homozygous for a T3 receptor defect, resulting in a complex clinical picture of tissue-specific hyperthyroidism and hypothyroidism. There was no evidence of significant alteration in thyroid physiology, including serum concentrations of basal and TRH stimulated TSH or echocardiographic parameters measuring systolic time interval. We conclude that D-T4 at a daily dose of 6 mg (0.65 mg/kg) was ineffective in this*boy with homozygous dominant negative thyroid hormone resistance.
CASE REPORT
INTRODUCTION
Several reported (1-6) describing perhaps
resistance have three types of resistance
This kindred has been presented previously (6). The propositus the firstborn child to first cousins who both had mild GTHR. The pregnancy was complicated by fetal tachycardia and preterm labor at 35 weeks gestation, resulting in an unsupervised home delivery. The birth weight was 1480 g, length 41.5 cm. The neonatal course included tachycardia, respiratory distress, polycythemia, patent ductus arteriosus, hyperbilirubinemia, hypofibrinoginemia, a prominent stare, bicuspid valve insufficiency, right inguinal hernia, and left hydrocele. Goiter was not appreci¬ ated initially. A metabolic screen obtained at 3 days of age revealed T4 of 432 nmol/L (33.6 µg/dL) and TSH of 299 mU/L. I23I uptake and scan of the thyroid demonstrated increased uptake (50% at 24 h), with a moderately enlarged gland. The hemiskeletal bone age was less than term at 4 weeks of age. He had continued signs of thyrotoxicosis (tachycardia, poor weight gain, frequent stools) and hypothyroidism (developmental and skeletal maturation delay) and subsequently developed a large, smooth, soft goiter, noncommu-
kindreds with thyroid hormone
been states,
was
comprising a clinical spectrum: (a) generalized thyroid hormone resistance (GTHR), (b) selective pituitary thyroid hormone resistance (SPTHR), and (c) peripheral thyroid hormone resistance (PTHR) (3-8). Resistance to the metabolic effects of thyroxine (L-T4) may be tissue dependent (9). The dextroisomer of L-T4 (dextrothyroxine; D-T4) is metab¬ olized to D-T, (10) and reverse D-T,. The former binds to the T, receptor with 13% of the affinity of L-T, in vitro (11) and is metabolically less active than the levoisomer. We report our recent experience with D-T4 in treating a boy with evidence of homozygous (dominant negative) autosomal dominant thyroid hormone resistance due to a three base pair (bp) deletion in the c-erbA beta-thyroid hormone receptor gene resulting in the loss of threonine codon 332 (12) of the thyroid hormone receptor. Our objectives in treating this patient were to decrease the clinical manifestations of hyperthyroidism in order to optimize growth, caloric use, and neurologic development and to mini¬ mize the potential risk of pituitary hyperplasia.
Department of Pediatrics, Section Hospital. St. Petersburg, Florida. Presented in part
at
of
the International
Endocrinology. University
nicating hydrocephalus (requiring
a
intermittent seizures controlled with growth retardation.
of South Florida
College
Symposium on Advances in Perinatal Thyroidology, 15
of Medicine.
ventriculoperitoneal shunt), phénobarbital, and marked
Tampa,
December 2, 1990,
Florida, and All Children's
Longboat Key.
Florida.
16
SCHWARTZ AND BERCU
Assays and procedures
isomerie forms of T4 were unavailable. Therefore, TG concentrations were used as an index of thyroid function, since TG concentrations are positively correlated with thyroid hyperfunction (13). Serum concentrations of angiotensin-converting enzyme and sex hormone-binding globulin (data not shown) and TBG and cholesterol did not change signifi¬ cantly with D-T4 therapy. measure
serum
Serum concentrations of T4 and T, were measured by radio¬ 1987 to 1989. after which an enzymelinked assay was used. The hypothalamic-pituitary-thyroid axis was assessed with TRH (7 µg/kg i.V.). Serum concentrations of
immunoassay (RIA) from
thyroglobulin (TG), thyroxine-binding globulin (TBG), freeT4, and free T, were measured by Nichols Institute (San Juan Capistrano, CA). Free hormones were measured by equilibrium dialysis. Echocardiography was performed as an assessment of func¬ tional peripheral thyroid status first using a Toshiba 65 and later a Toshiba 140 system. The preejection period (PEP) was the period from the initiation of the Q wave on the simultaneous electrocardiogram to aortic valve opening. The left ventricular ejection time (LVET) was the time between opening and closure
DISCUSSION The therapeutic approach to patients with SPTHR is to decrease pituitary TSH secretion in order to decrease secretion of thyroid hormones and improve symptoms. Indirect methods to lower TSH secretion by modulating the T, receptor have met with variable success and include the use of exogenous L-T4 and L-T, and analogs to L-T,, including 3,5,3'-triiodothyroacetic acid (TRIAC) (4,14-16). Treatment may not be required in patients with mild GTHR. In those clinically mildly hypothyroid patients, these thyromimetic agents often result in clinical improvement and lowered serum concentration of TSH. Direct methods to decrease TSH secretion include somatostatin and dopaminergic analogs (4,17-19). Our patient showed no change in TSH secretion during acute somatostatin infusion (data not shown). Because of the extraordinary elevations in thyroid hormone concentrations, therapy with supplemental thyromi¬ metic agents did not seem to be warranted. Hamonetal. reported using D-T4 in treating a 15-month-old boy with mild SPTHR and accelerated height velocity and bone age advancement who failed a trial of TRIAC (20). There was clinical improvement, decreased serum TSH and L-T4 concentrations [4.6 to 1.8 mU/L and 230 to 93 nmol/L (18.0 to 7.3 µg/dL, stereospecific assay), respectively] and slowing of growth rate and degree of skeletal maturation after 16 months of D-T4 (Dynothel, 5 mg/day) (20). Dorcy et al., using low doses of D-T4 in three adults with mild SPTHR, described lessened symptoms of thyrotoxicosis and lowered TG as well as basal and peak TSH concentrations (21), although their patients received D-T4 concurrently with PTU
of the aortic valve.
Study approval was obtained from the institutional review boards of the University of South Florida College of Medicine and All Children's Hospital. Parents signed informed consent. The patient underwent two separate trials of D-T4. D-T4 first was provided as Choloxin, generously provided by The Boots Company (Shreveport, LA). In the second trial, D-T4 was
provided as Dynothel, generously provided by Henning (Berlin, Germany). During each trial, the patient was reassessed regu¬ larly, and the dosage of D-T4 was adjusted based on clinical response and biochemical parameters.
RESULTS The clinical and laboratory course before initiation of D-T4 is shown in Table 1. Normal feedback of the pituitary-thyroid axis was shown by marked lowering of T4 with concomitant eleva¬ tion in TSH while the child inadvertently received approxi¬ mately 10 times the prescribed dose of propylthiouracil (PTU) for 1 week. Parameters of thyroid physiology, including cardiac tissue sensitivity, during both D-T4 trials are shown in Table 2 and Figures 1 and 2. Methods to specifically differentiate and
Table 1. Biochemical
and
Treatment Course of Child with GTHR Before Therapy with
TSH
Age
T4
(mU/L)
(nmol/L)
3 days 25 days 1.5 months 2.3 months 4.3 months 9.5 months 11.5 months 19.5 months 33.5 months Normal range
299 389 670 395 290 198 160 155 102 0.5-5.0
432
653b 37 273 822 336 252 331
641" 94-194
D-T4
(nmol/L)
A"
20.7 1.0 15.3 17.6 17.3 9.1 12.4 15.3 1.6-4.1
