Familial partial peripheral and pituitary resistance to thyroid hormone: a frequently missed diagnosis?

The diagnosis of partial peripheral and pituitary resistance to thyroid hormone was ultimately made in two boys, 7 and 9 years of age, and a 10-year-old girl who had goiters and hyperthyroxinemia. The boys were treated with propythiouracil and/or thyroidectomy or iodine 131 for suspected thyrotoxicosis but had poorly suppressible serum thyroid-stimulating hormone (TSH) post treatment in spite of the usual L-thyroxine replacement. The girl had increasing goiter size while receiving propylthiouracil, 100 mg every eight hours. These findings led to reevaluation of thyroid hormone dynamics in these children and their families. Twelve additional family members, 3 to 38 years of age, compatible with an autosomal dominant inheritance, were also found to have peripheral and pituitary resistance to thyroid hormone. All affected individuals had elevated serum thyroxine and triiodothyronine levels, normal to slightly elevated triiodothyronine resin uptakes, and a nonsuppressed serum TSH. The five individuals who were given thyrotropin-releasing hormone showed exaggerated TSH responses, which normalized on L-thyroxine therapy. Misdiagnosis in six of 15 family members led to significant morbidity (hypothyroidism, delayed growth, and therapy risk). A nonsuppressed serum TSH in a patient with suspected thyrotoxicosis should lead to suspicion of this disorder. Appropriate management for this condition includes L-thyroxine therapy to decrease goiter size and normalize TSH responses to thyrotropin-releasing hormone.     

Successful therapy with L-T4 in a 5 year-old boy with generalized thyroid hormone resistance

Resistance to thyroid hormone (RTH) is a rare dominantly inherited disorder caused by mutations in the thyroid hormone receptor beta gene which lead to impaired tissue responsiveness to thyroid hormone (TH). RTH is characterized by elevated free thyroid hormone and unsuppressed thyrotropin (TSH) levels. Two types of the disorder have been recognized: selective pituitary resistance and generalized resistance to TH (GRTH). Triiodothyroacetic acid has been used in patients showing hypermetabolism, and L-T4 treatment in high doses has been suggested in GRTH if patients have signs of clinical hypothyroidism such as growth retardation and developmental delay. The outcome of long-term treatment of GRTH with L-T4 has not yet been reported. We report a 5 year-old boy who presented with severe growth retardation, fatigue and speech delay. He had hyperactivity despite feeling tired easily. Elevated TH levels with unsuppressed TSH and delayed bone age were determined by laboratory evaluation and he was diagnosed as GRTH. There was no clinicical evidence of hypermetabolism. We could not demonstrate any mutation in thyroid receptor beta1, beta2 or alpha gene of this patient and his parents. L-T4 treatment was started at conventional doses (6 microg/kg), and after 3 months of treatment T4 and TSH levels were suppressed successfully. In 12 months of treatment, no side effects were detected and surprisingly clinical symptoms improved without requirement for high doses of L-T4.     

Syndrome of Generalized (Peripheral Tissue and Pituitary) Resistance to Thyroid Hormone

Generalized resistance to thyroid hormone (GRTH), or Refetoff syndrome, is a disease in which peripheral tissues show resistance to thyroid hormone. Three patients with this disease were investigated. Cases 1 and 2 involved identical 7-year-old female twins and case 3, a 5-year-old girl. All three patients had goiters, and cases 1 and 2 had sensorineural deafness. In all three, the blood levels of T₄, free T₄, and T₃ were high, while the blood levels of TSH were normal or slightly elevated. The responses shown by blood levels of the thyroid hormone and TSH to administration of propylthiouracil and T₃ suggest that the regulating mechanism in the hypothalamic-pituitary-thyroid system was functional. Upon administration of T₃, no sign of hyperthyroidism was observed.     

Przysadkowa oporność na hormony tarczycy u 12-letniej dziewczynki

Hypertyroxinemia with normal TSH concentrations is a difficult to solve clinical problem. Such results of thyroid function tests may suggest pituitary resistance to thyroid hormones. We report a 12-year-old girl with this syndrome who was admitted due to tachycardia, goiter and elevated concentrations of total and free thyroid hormones in the absence of TSH suppression. The key test in the rapid diagnosis was the analysis of thyroid hormone receptor gene THRB mutation. The increasing availability of these tests and their relatively low cost allow to avoid excessive diagnostics, bringing significant clinical and economic benefits.     

A mutation in thyroid hormone receptor beta causing "resistance to thyroid hormone" in a neonate

Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by reduced tissue responsiveness to thyroid hormones. The main defects are due to mutations in thyroid hormone receptor beta (TRbeta). A male, term neonate was admitted because of indirect hyperbilirubinemia and polycythemia. Physical examination revealed ophtalmopathy. High serum T? with unsupressed thyroid stimulating hormone (TSH) levels suggested RTH. In this presented case, A317T mutation was detected on exon 9 of the TRb-1 gene and precise diagnosis had been confirmed with genetic testing. In neonates and infants exhibiting hypo or hyperthyroidism features with increased circulating levels of thyroid hormones with a normal or increased serum TSH concentration should raise the suspicion of RTH.     

A case of dyshormonogenetic goiter complicated with growth hormone deficiency

A 17-year-old male patient with dyshormonogenetic goiter complicated with follicular adenoma and growth hormone deficiency is described. He had short stature (-2.3 SD), diffuse goiter and a particularly large nodule in the right lobe of the thyroid gland. The endocrinological studies revealed slight hypothyroidism. He underwent surgical removal of the tumor, diagnosed histopathologically as follicular adenoma, embryonal type; and the diffuse goiter was diagnosed as dyshormonogenetic goiter. It was speculated that long-term hypersecretion of thyroid stimulating hormone (TSH) caused adenoma in the thyroid gland. Although the goiter disappeared after oral thyroxine replacement therapy, his height gain remained poor. Then, he was diagnosed partial growth hormone deficiency, and growth hormone therapy improved his height gain. It has been reported that a high percentage of patients with congenital hypothyroidism have additional anomalies. This is, however, the first reported case of dyshormonogenetic goiter complicated with growth hormone deficiency.     

Alterations of neonatal thyroid function

Recent progress has been made in understanding the pathogenesis of neonatal thyroid disorders. Autosomal recessive inheritance of mutations of the thyroid peroxidase and thyroglobulin genes has been described in some patients with congenital hypothyroidism (CH) and a family history of CH. Autosomal recessive inheritance of mutations of the thyrotrophin (TSH) receptor gene has also been reported in patients with CH and thyroid hypoplasia, and autosomal dominant mutations of the PAX8 gene have been described in patients with different forms of thyroid dysgenesis. These discoveries are important for patients with CH diagnosed by neonatal screening, as these patients will have normal fertility. The molecular genetic analysis of mutations of the TSH gene in patients with familial and sporadic cases of isolated central CH, who are missed by TSH screening programmes, now enables rapid diagnosis and appropriate therapy in the neonate. In newborn infants with severe non-autoimmune hyperthyroidism, autosomal dominant gain-of-function mutations in the TSH receptor gene have been demonstrated. In these patients, molecular genetic studies are extremely helpful in therapeutic decision making, as early thyroid ablation is the only effective treatment that avoids the sequelae of long-term hyperthyroidism. Molecular genetic studies are therefore useful in the diagnostic work-up of neonatal thyroid alterations.     

Assessment of goiter prevalence, iodine status and thyroid functions in school-age children of rural Yusufeli district in eastern Turkey

According to previous studies, Turkey has generally been accepted as a moderate endemic iodine deficient country. However, it has recently been reported that there are regions in Turkey where iodine deficiency is more severe than previously known. The current study was aimed at ascertaining the goiter prevalence by thyroid volumes, iodine status and thyroid functions in school-age children living in an area which is suspected to have moderate or severe iodine deficiency. Overall goiter was found in 47.6% of children, in 22.8% of girls and in 24.8% of boys. Mean thyroid volumes did not differ significantly according to sex. Significant correlation was found between thyroid volume and body surface area and age. There was a negative correlation between the urinary iodine concentration and thyroid volume (r = 0.45, p < 0.01). Median urinary iodine concentrations in subjects with and without goiter were 20 microg/dl and 5.2 microg/dl, respectively. While median urinary iodine levels of the subjects with goiter were consistent with severe-moderate iodine deficiency, levels in subjects without goiter were comparable to moderate-mild iodine deficiency. None of the subjects had the signs or symptoms of hyper-or hypothyroidism. The differences in the mean values of thyroid hormones and TSH levels between subjects with or without goiter were not significant (p > 0.05). No correlation was found between urinary iodine concentrations and thyroid hormone levels. A weak correlation was found between urinary iodine concentration and TSH levels (r = 0.12, p = 0.05). Individuals with goiter were investigated etiologically: biochemical hypothyroidism was detected in 2%, compensated hypothyroidism in 12.6%, autoimmune thyroiditis in 2%, nodular goiter in 3% and isolated high TSH level with autoimmune thyroiditis in 0.08%. In conclusion, although a salt iodization program has been started in Turkey, our study indicates that some regions with severe iodine deficiency are still present. This research suggests that this program should be re-evaluated for remote areas with self-contained economic systems, and should be expanded and more effectively applied nation-wide.     

Thyroid function in term newborn infants with congenital goiter.

Eighty-four term newborn infants without goiter and 45 newborn infants with congenital goiter were studied with regard to thyroid function. The radiologic development of the femoral and tibial epiphyses was evaluated in those with goiter. Fifty-eight percent of the patients had retarded bone age, markedly elevated TSH levels, elevated TBI, decreased total T4I, and decreased PBI values. Forty-two percent of newborn infants with congenital goiter had a normal bone age, normal values for TSH, PBI, and total T4I, and elevated values for TBI. It is concluded that the 58% of the newborn infants with congenital goiter had subtle hypothyroidism. They require substitution therapy with thyroid hormones in order to avoid possible retardation of normal brain development. Patients with congenital goiter who have no biochemical evidence of hypothyroidism should also be treated with thyroid hormones to achieve rapid regression of goiter.     

Hyperfunctioning thyroid nodules in children

We studied two cases of hyperfunctioning thyroid nodules in children. A 9-year-old girl and an 11-year-old girl had thyroid masses in otherwise nonpalpable thyroid glands. Scintiscan showed hyperfunctioning thyroid nodules. The former patient had elevated values for T4 and T3, and plasma thyrotropin (TSH) level failed to respond to stimulation with thyrotropin releasing hormone (TRH), whereas the latter patient had normal values for T4, and T3 and plasma TSH response to TRH was normal. After the surgical removal of nodules, scintiscan exhibited radioactivity in the contralateral lobe of the thyroid gland in the former and in the ectopic thyroid tissue in the latter. Results of microscopic examinations of thyroid nodules were consistent with adenomatous goiter.     

Thyroid hormone abnormalities at diagnosis of insulin-dependent diabetes mellitus in children

Comprehensive evaluation of thyroid hormone indices was performed in 58 children with insulin-dependent diabetes mellitus (IDDM) at the time of diagnosis and prior to insulin therapy. Two patients were found to have primary hypothyroidism, with markedly elevated TSH and very low T4, free T4, T3, and reverse T3 concentrations. The remaining 56 patients had the transient alterations in thyroid hormone indices that are characteristic of "euthyroid sick" or "low T3" syndrome. Mean TSH and reverse T3 values were significantly higher and the mean T3, T4, and free T4 levels were significantly lower than those observed in the control population. Ten of the diabetic patients had elevated TSH concentrations and normal or low free T4 values; eight had normal TSH levels and low T4 and free T4 values. The remainder of the group had thyroid indices compatible with abnormal peripheral metabolism of thyroid hormones. Elevated titers of antimicrosomal antibodies were found in 16% of the children with IDDM. We conclude that abnormal peripheral metabolism and altered hypothalamic-pituitary function are responsible for the transient changes in thyroid hormone indices in patients with untreated IDDM. The most reliable indicators of concomitant primary hypothyroidism in untreated IDDM are markedly elevated TSH and low reverse T3 values.     

Thyroid hormone profile in children with goiter in an endemic goiter area

The thyroid hormone profile was investigated in goitrous schoolchildren aged 6-11 years living in Antalya, an area with mild/ moderate iodine deficiency. With few exceptions, the serum levels of T4 and TSH were in the normal range in children with different grades of goiter. Compensatory elevated T3 levels were detected in 24% of the subjects. Thyroid hormones did not differ significantly with respect to the urinary iodine (UI) level. No correlations were found between thyroid volume, UI excretion level and thyroid hormones. It was concluded that thyroid hormones, except compensatory T3 elevation in some subjects, were not affected significantly in a mild/moderate iodine deficient area.     

Alterations of neonatal thyroid function

Grüters A, Krude H, Biebermann H, Liesenkötter KP, Schöneberg T, Gudermann T. Alterations of neonatal thyroid function. Acta Pædiatr 1999; Suppl 428: 17–22. Stockholm. ISSN 0803–5326
Recent progress has been made in understanding the pathogenesis of neonatal thyroid disorders. Autosomal recessive inheritance of mutations of the thyroid peroxidase and thyroglobulin genes has been described in some patients with congenital hypothyroidism (CH) and a family history of CH. Autosomal recessive inheritance of mutations of the thyrotrophin (TSH) receptor gene has also been reported in patients with CH and thyroid hypoplasia, and autosomal dominant mutations of the PAX8 gene have been described in patients with different forms of thyroid dysgenesis. These discoveries are important for patients with CH diagnosed by neonatal screening, as these patients will have normal fertility. The molecular genetic analysis of mutations of the TSH gene in patients with familial and sporadic cases of isolated central CH, who are missed by TSH screening programmes, now enables rapid diagnosis and appropriate therapy in the neonate. In newborn infants with severe non-autoimmune hyperthyroidism, autosomal dominant gain-of-function mutations in the TSH receptor gene have been demonstrated. In these patients, molecular genetic studies are extremely helpful in therapeutic decision making, as early thyroid ablation is the only effective treatment that avoids the sequelae of long-term hyperthyroidism. Molecular genetic studies are therefore useful in the diagnostic work-up of neonatal thyroid alterations. □ Congenital hypothyroidism, molecular pathogenesis, neonatal hyperthyroidism     

Concurrent occurrence of chronic lymphocytic thyroiditis with hypothyroidism and growth hormone deficiency in a Turner's syndrome patient

BACKGROUND: Concurrent deficiencies of three hormones in patients with Turner's syndrome (TS) have rarely been reported. Here, we describe a case of a young girl who had Turner's syndrome with concomitant chronic lymphocytic thyroiditis, growth hormone deficiency, and hypothyroidism with cardiopericarditis. CASE: An 11-year-old girl was referred to the outpatient clinic because of short stature, ochriasis, and cardiopalmus. Her ultrasound revealed absence of ovarian tissue. Karyotype examination suggested Turner's syndrome with sex hormone deficiency. She was found to have an abnormal thyroid gland and elevated thyroid stimulating hormone (TSH). A positive thyroid autoantibody titer confirmed the diagnosis of chronic lymphocytic thyroiditis with hypothyroidism. Furthermore, her growth hormone levels were well below normal. DIAGNOSIS: A multi-endocrine disorder, i.e., Turner's syndrome with chronic lymphocytic thyroiditis, growth hormone deficiency, and hypothyroidism with cardiopericarditis was diagnosed. Growth hormone and thyroxin substitution therapy was suggested.     

Hyperthyroxinämie mit kardialer Symptomatik

Resistance to thyroid hormone (RTH) is a rare autosomal dominant inherited disease, which is usually caused by mutations in the TRβ-gene. The clinical presentation of RTH is highly variable and patients can show signs of euthyroidism, hypothyroidism and/or hyperthyroidism. We report on a 12¹¹/₁₂ year old girl who was admitted to hospital with tachycardia. Laboratory tests showed high levels of serum free T3 and free T4 in the presence of non-suppressed TSH concentrations. Further investigations, including molecular genetic tests, were then performed and revealed a rare case of thyroid hormone resistance. Our case report demonstrates that patients with RTH may manifest only cardiovascular symptoms.     

Cyclical combination chemotherapy and thyroid function in patients with advanced hodgkin's disease

Clinical and biochemical assessment of thyroid function was undertaken in patients with Hodgkin's disease at designated points following diagnosis. At diagnosis, two of 20 patients had either abnormally low routine thyroid indices, or elevated thyroid stimulating hormone (TSH) levels that were not due to iodine-based investigations. Following lymphography, 76.5% of patients had TSH levels that remained elevated for a median period of 3 months. No detectable thyroid dysfunction was induced during chemotherapy. Fifty-four patients were studied at a median time of 35 months after chemotherapy. One euthyroid patient had a nodular goitre, and one had abnormal thyroid indices. TSH levels were elevated in 44% of patients, although the median TSH level for the group was normal. Half the patients had abnormal TRH stimulation tests. Sixty patients were studied after irradiation and chemotherapy. Four patients had clinical thyroid dysfunction, and 10% of routine thyroid indices were abnormal. TSH levels were abnormal in 80%, with a markedly elevated median level. All thyroid releasing hormone stimulation tests were abnormal.     

Hyperthyrotropinemia in a neonate with normal thyroid hormone levels: the earliest diagnostic clue for pseudohypoparathyroidism

A neonatal case of hyperthyrotropinemia is described in association with pseudohypoparathyroidism (PHP). This girl was found to have high serum thyrotropin (TSH) on screening, though serum thyroid hormones were within the normal ranges throughout the observation. The patient's TSH remained above the normal limit until 5 years of age, when she suffered from hypocalcemic tetany and was diagnosed as type-1 PHP on the basis of responsiveness to parathyroid hormone. She also had stigmata of Albright's hereditary osteodystrophy. The results demonstrate that elevated TSH, although thyroid hormone concentrations are normal and medication is not indicated, may be one of the earliest diagnostic clues for PHP.     

Autoimmunthyreopathien bei Kindern und Jugendlichen mit Typ-1-Diabetes Häufigkeit und sinnvolles Screening

Background. Children and adolescents with type 1 diabetes are at increased risk for the development of autoimmune thyroid disease (Hashimoto thyroiditis and Grave's disease). Recommendations for screening have been very inconsistent. Method. Between 1996 and 1999, yearly determinations of serum TSH, fT4, fT3, thyroid peroxidase (TPO-) and thyroglobulin (Tg-) antibodies were done in 155 children and adolescents with diabetes. In those who were positive for thyroid antibodies and/or had a goiter thyroid sonography was performed. Specific therapy was instituted when overt hypo- or hyperthyroidism or subclinical hypothyroidism with goiter was present. No treatment was given to euthyroid patients who had positive thyroid antibodies but no goiter. Results. Between 1996 and 1999, autoimmune thyroiditis was diagnosed in 7 out of 155 children (all females). Hashimoto thyroiditis was present in 4, Grave's disease in 2 and thyroid antibody negative transient hyperthyroidism in one. Median age at diagnosis was 10.9 years, median duration of diabetes 3.1 years. The long-term course of thyroid autoantibody titers varied widely, there was no correlation with activity of hypo- or hyperthyroidism, predominant were TPO- antibodies. Four euthyroid children had elevated thyroid antibodies only, none developed a goiter or thyroid dysfunction so far. One child had subclinical hypothyroidism without thyroid antibodies and was treated with iodine. Of note were markedly increased HbA1c levels coincident with overt hyperthyroidism which decreased once euthyroidism was achieved. Conclusion. Routine screening for autoimmune thyroid disease in children and adolescents with diabetes is necessary. At onset of diabetes, thyroid function and antibodies should be determined to identify patients at risk. During follow-up, search for symptoms and signs of hypo- or hyperthyroidism or goiter as well as a determination of TSH once yearly is sufficient. If abnormal findings are present an extended work-up is necessary (see Fig. 1). Unexplained high HbA1c levels may be caused by unrecognised hyperthyroidism.     

Severe psychomotor and metabolic damages caused by a mutant thyroid hormone receptor alpha 1 in mice: can patients with a similar mutation be found and treated?

Individuals suffering from the resistance to thyroid hormone syndrome (RTH) have a mutation in thyroid hormone receptor (TR) beta. Surprisingly, no patient with a mutation in TRalpha1 has been found. To facilitate their identification, animal models with a RTH-like mutation in TRalpha1 have been generated. The mutations introduced into the mouse decrease affinity to ligand, resulting in a 'receptor-mediated hypothyroidism' in tissues expressing the mutant receptor: brain, heart and bone. The mice present minor perturbances in thyroid hormone homeostasis, but show major aberrancies in postnatal development, psychomotor behaviour and metabolism. These parameters are akin to those seen in endemic cretinism and untreated congenital hypothyroidism. Treatment of the mice with high doses of triiodothyronine leads to normalization or amelioration of the dysfunctions when applied at adequate developmental periods. CONCLUSION: Our studies on mice suggest the existence of a potentially debilitating disease caused by a mutant TRalpha1, and provide insights for identification and treatment of corresponding patients.     

Genetic defects in thyroid hormone synthesis.

Thyroid hormone synthesis requires a normally developed thyroid gland, a properly functioning hypothalamic-pituitary-thyroid axis, and sufficient iodine intake. This article focuses on genetic defects in this axis. Defects that are primarily of developmental origin are discussed in our associated article in this issue. Defects in hormone synthesis usually are associated with the development of a goiter, provided that the bioactivity and action of thyrotropin (TSH) are not impaired. In contrast, hypoplasia of the gland may be caused by developmental defects, bioinactive TSH, or resistance to TSH at the level of the receptor or its signaling pathway. At the other end of the spectrum, hyperthyroidism may result from gain of function mutations in genes regulating growth and function.