Studies on the Thyroidal Defect in an Atypical Form of Pendred's Syndrome* WILLIAM T. CAVE, JR., AND JOHN T. DUNN Division of Endocrinology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22901 ABSTRACT. A 52-yr-old woman and her 47-yr-old brother both had large goiters, short stature, nerve deafness, and mild intellectual impairment. Serum levels of thyroid hormones were normal (sister) on borderline low (brother), urinary I27I levels were normal, and perchlorate discharge tests were negative. After administration of 12&I, we found normal uptakes and retention of isotope by the thyroid, normal serum half-lives for PB 125I, and absence of labelled iodotyrosines in serum or
to each other and to thyroglobulin samples from normal humans when examined by gel electrophoresis both before and after reduction and alkylation. However, the three thyroglobulins from the same gland differed significantly from one another in their composition of most amino acids. This finding indicates that there can be heterogeneity in the protein portion of thyroglobulin, and since the three samples of thyroglobulin were from the same individual, this heterogeneity was probably not of genetic origin. In these patients we could not demonstrate any of the well-established biochemical defects associated with familial goiter. An abnormality in thyroglobulin structure remains a distinct possibility, but we must defer conclusions until there is more known about thyroglobulin heterogeneity and its relationship to hormone biosynthesis. (J Clin Endocrinol Metab 41: 590, 1975)
urine.
Particulate fractions from both glands had peroxidase activity by in vitro tests for guaiacol oxidation and tyrosine iodination. Samples from different parts of the sister's gland showed a correlation between peroxidase activity in vitro and radioiodine uptake in vivo. We made three separate preparations of thyroglobulin from the sister and one from the brother by gel filtration on 4% agarose. These were similar
P
AST efforts to classify familial goiter have listed the association of congenital deafness and goiter as a specific genetic entity (2), termed Pendred's syndrome after the clinician who first reported it (3,4). Following the description by Morgans and Trotter (5) of defective binding of iodide by the thyroids of many of these patients, Pendred's syndrome has usually been defined as a triad composed of familial goiter, abnormal perchlorate discharge test, and congenital deafness (6). Initially it was anticipated that the intrathyroidal defect would be a genetic abnormality in thyroidal peroxidase, but no significant lack of this enzyme has been identified despite careful in vitro studies of thyroid biopsies (7-9). In fact, in most cases no protein abnormality of any sort had been found (8-10) and the biochemical defect in Pendred's has remained unknown (6).
Received March 17, 1975. * An abstract of part of this work has been published (1).
We have recently studied in detail two siblings with an atypical form of Pendred's syndrome, characterized by familial goiter, deafness, and a negative perchlorate discharge test. This paper details clinical and chemical investigations into t h e nature of their thyroidal defect. Case Reports A 52-yr-old white woman C.S. and her 47-yr-old brother R.S. were thefirstand third of 8 siblings (Fig. 1). The parents were reportedly third cousins and the mother had a thyroid nodule, but further details are not known. The other siblings included 2 infants dying of unknown causes and another female deaf-mute cretin, who died at the age of 40 yr of gastric carcinoma. This latter sibling, the second born, had had hypothyroidism documented by a low basal metabolic rate 20 yr before death, and thyroid extract had been recommended. Her brief hospital record never mentioned the presence of goiter. We examined the youngest sister, M.R., and found normal physical and mental development but a thyroid of twice normal size, which had not been recognized previously.
590
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THYROID IN ATYPICAL PENDRED'S SYNDROME
L^ FIG. 1. Pedigree diagram. C.S. and R.S. are respectively the first and third of the eight siblings.
591
J
DECEASED 9)
NORMAL DEAF-MUTE & GOITER ABNORMAL THYROID
Deafness had been noted in both C.S. and R.S. at birth, and goiters had been evident since early adolescence. Both received remedial education at a school for the deaf, but more advanced training was not attempted because of apparent mental retardation. On physical examination both patients were short, normally developed adults with pendulous goiters and mild mental retardation (Fig. 2). R.S. was 61 inches high and weighed 130 lbs. C.S. was 57 inches high and weighed 114 lbs. Routine laboratory studies were within normal limits. Karyotype analyses were normal. Audiologic testing of both C.S. and R.S. revealed profound sensorineural hearing loss. In R.S. tomogranis of the inner ear (11,12) were done, but failed to demonstrate any cochlear defect. On psychologic testing both patients had IQ's of approximately 70. Thyroid function studies1 are listed in Table 1. Following the initial metabolic evaluation, both patients underwent excisional biopsies of their massive goiters, yielding 286 g of tissue from C.S. and 170 g from R.S. Histologically, 1 Abbreviations for tests of thyroid function are as recommended by the American Thyroid Association (13); the other abbreviation used in this paper is TG (thyroglobulin).
the functioning tissue from both glands show marked heterogeneity consisting of enlarged colloid-filled follicles and regions of microfollicular adenomatosis. In addition, both glands showed focal fibrosis, hemorrhage, and calcification. In R.S. the majority of the gland consisted of a large necrotic cyst with only a rim of functioning tissue. Materials and Methods Clinical studies. Routine serum tests of thyroid function included TSH and T3 by radioimmunoassays, T4 by competitive protein binding, T3 resin uptake, thyroxine-binding globulin (TBG), and assays for antibodies to thyroglobulin or microsomal antigens. Perchlorate discharge studies were performed by the Department of Nuclear Medicine, University of Virginia, using a protocol that gave 100 mg of perchlorate orally 90 minutes after an oral dose of 15 fiCi 131J
Three days before surgery C.S. received 500 /uCi (125I)NaI orally. R.S. received the same dose 4 days before surgery. Daily urine collections and serum samples were obtained and their isotope content measured in a Packard well-type counter. Following excision, the glands were weighed and those portions not used for histological examination were stored at - 7 0 C.
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CAVE AND DUNN
592
JCE & M . 1975 Vol 41 . No 3
FIG. 2. Patients C.S. and R.S. with atypical. Pendred's syndrome, shown with M.R. (on left), their goitrous but otherwise normal sister.
Iodoprotein purification. Four TG preparations were made, three from different parts of the thyroid of C.S., designated TG (CS-I), TG (CS-II), and TG (CS-III), and one from R,S., TABLE 1. Laboratory tests on sera of patients C.S., R.S., and their sister M.R. C.S. T«(D) (5.2-14.3 /Kg/100 ml)
7.6
R.S. 3.2
T3(RIA) (60-190 ng/100 ml)
144
134
RT3U (25-35%)
26
32
TSH (
to each other and to thyroglobulin samples from normal humans when examined by gel electrophoresis both before and after reduction and alkylation. However, the three thyroglobulins from the same gland differed significantly from one another in their composition of most amino acids. This finding indicates that there can be heterogeneity in the protein portion of thyroglobulin, and since the three samples of thyroglobulin were from the same individual, this heterogeneity was probably not of genetic origin. In these patients we could not demonstrate any of the well-established biochemical defects associated with familial goiter. An abnormality in thyroglobulin structure remains a distinct possibility, but we must defer conclusions until there is more known about thyroglobulin heterogeneity and its relationship to hormone biosynthesis. (J Clin Endocrinol Metab 41: 590, 1975)
urine.
Particulate fractions from both glands had peroxidase activity by in vitro tests for guaiacol oxidation and tyrosine iodination. Samples from different parts of the sister's gland showed a correlation between peroxidase activity in vitro and radioiodine uptake in vivo. We made three separate preparations of thyroglobulin from the sister and one from the brother by gel filtration on 4% agarose. These were similar
P
AST efforts to classify familial goiter have listed the association of congenital deafness and goiter as a specific genetic entity (2), termed Pendred's syndrome after the clinician who first reported it (3,4). Following the description by Morgans and Trotter (5) of defective binding of iodide by the thyroids of many of these patients, Pendred's syndrome has usually been defined as a triad composed of familial goiter, abnormal perchlorate discharge test, and congenital deafness (6). Initially it was anticipated that the intrathyroidal defect would be a genetic abnormality in thyroidal peroxidase, but no significant lack of this enzyme has been identified despite careful in vitro studies of thyroid biopsies (7-9). In fact, in most cases no protein abnormality of any sort had been found (8-10) and the biochemical defect in Pendred's has remained unknown (6).
Received March 17, 1975. * An abstract of part of this work has been published (1).
We have recently studied in detail two siblings with an atypical form of Pendred's syndrome, characterized by familial goiter, deafness, and a negative perchlorate discharge test. This paper details clinical and chemical investigations into t h e nature of their thyroidal defect. Case Reports A 52-yr-old white woman C.S. and her 47-yr-old brother R.S. were thefirstand third of 8 siblings (Fig. 1). The parents were reportedly third cousins and the mother had a thyroid nodule, but further details are not known. The other siblings included 2 infants dying of unknown causes and another female deaf-mute cretin, who died at the age of 40 yr of gastric carcinoma. This latter sibling, the second born, had had hypothyroidism documented by a low basal metabolic rate 20 yr before death, and thyroid extract had been recommended. Her brief hospital record never mentioned the presence of goiter. We examined the youngest sister, M.R., and found normal physical and mental development but a thyroid of twice normal size, which had not been recognized previously.
590
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THYROID IN ATYPICAL PENDRED'S SYNDROME
L^ FIG. 1. Pedigree diagram. C.S. and R.S. are respectively the first and third of the eight siblings.
591
J
DECEASED 9)
NORMAL DEAF-MUTE & GOITER ABNORMAL THYROID
Deafness had been noted in both C.S. and R.S. at birth, and goiters had been evident since early adolescence. Both received remedial education at a school for the deaf, but more advanced training was not attempted because of apparent mental retardation. On physical examination both patients were short, normally developed adults with pendulous goiters and mild mental retardation (Fig. 2). R.S. was 61 inches high and weighed 130 lbs. C.S. was 57 inches high and weighed 114 lbs. Routine laboratory studies were within normal limits. Karyotype analyses were normal. Audiologic testing of both C.S. and R.S. revealed profound sensorineural hearing loss. In R.S. tomogranis of the inner ear (11,12) were done, but failed to demonstrate any cochlear defect. On psychologic testing both patients had IQ's of approximately 70. Thyroid function studies1 are listed in Table 1. Following the initial metabolic evaluation, both patients underwent excisional biopsies of their massive goiters, yielding 286 g of tissue from C.S. and 170 g from R.S. Histologically, 1 Abbreviations for tests of thyroid function are as recommended by the American Thyroid Association (13); the other abbreviation used in this paper is TG (thyroglobulin).
the functioning tissue from both glands show marked heterogeneity consisting of enlarged colloid-filled follicles and regions of microfollicular adenomatosis. In addition, both glands showed focal fibrosis, hemorrhage, and calcification. In R.S. the majority of the gland consisted of a large necrotic cyst with only a rim of functioning tissue. Materials and Methods Clinical studies. Routine serum tests of thyroid function included TSH and T3 by radioimmunoassays, T4 by competitive protein binding, T3 resin uptake, thyroxine-binding globulin (TBG), and assays for antibodies to thyroglobulin or microsomal antigens. Perchlorate discharge studies were performed by the Department of Nuclear Medicine, University of Virginia, using a protocol that gave 100 mg of perchlorate orally 90 minutes after an oral dose of 15 fiCi 131J
Three days before surgery C.S. received 500 /uCi (125I)NaI orally. R.S. received the same dose 4 days before surgery. Daily urine collections and serum samples were obtained and their isotope content measured in a Packard well-type counter. Following excision, the glands were weighed and those portions not used for histological examination were stored at - 7 0 C.
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CAVE AND DUNN
592
JCE & M . 1975 Vol 41 . No 3
FIG. 2. Patients C.S. and R.S. with atypical. Pendred's syndrome, shown with M.R. (on left), their goitrous but otherwise normal sister.
Iodoprotein purification. Four TG preparations were made, three from different parts of the thyroid of C.S., designated TG (CS-I), TG (CS-II), and TG (CS-III), and one from R,S., TABLE 1. Laboratory tests on sera of patients C.S., R.S., and their sister M.R. C.S. T«(D) (5.2-14.3 /Kg/100 ml)
7.6
R.S. 3.2
T3(RIA) (60-190 ng/100 ml)
144
134
RT3U (25-35%)
26
32
TSH (
