A novel mutation of the signal peptide of the preproparathyroid hormone gene associated with autosomal recessive familial isolated hypoparathyroidism.

We report a novel mutation of the signal peptide of the prepro-PTH gene associated with autosomal recessive familial isolated hypoparathyroidism. The proposita presented with neonatal hypocalcemic seizures. Serum calcium was 1.5 mmol/L (normal, 2.0-2.5); phosphate was 3.6 mmol/L (normal, 0.9-1.5). She was born to consanguineous parents. A few years later, 2 younger sisters and her niece presented with neonatal hypocalcemic seizures. Their intact PTH levels were undetectable during severe hypocalcemia. Genomic DNA from the proposita was sequenced all exons of the prepro-PTH gene. A replacement of thymine with a cytosine was found in the first nucleotide of position 23 in the 25-amino acid signal peptide. This results in the replacement of the normal Ser (TCG) with a Pro (CCG). Genotyping of family members was carried out by identification of a new MspI site created by the mutation. Only affected family members were homozygous for the mutant allele, whereas the parents were heterozygous, supporting autosomal recessive inheritance. As this mutation is at the -3 position in the signal peptide of the prepro-PTH gene, we hypothesized that the prepro-PTH mutant might not be cleaved by signal peptidase at the normal position, and it might be degraded in rough endoplasmic reticulum.

Familial dysalbuminemic hypertriiodothyroninemia: a new, dominantly inherited albumin defect.

We report the abnormal albumin in members of a Thai family that presented with high serum total T3 but not T4 when measured by radioimmunoassay. In contrast, total T3 values were very low when measured by ELISA and chemiluminescence. The subjects have no goiter, and clinically euthyroid. Their serum free T4, free T3, and TSH were normal. Spiking of T3 to affected serum showed good recovery by radioimmunoassay, but very poor recovery by ELISA and by chemiluminescence. The immunoprecipitation with labeled T3 bound to albumin showed high percent precipitation in affected serum. T3-binding studies showed that the association constant of serum albumin in affected subjects was 1.5 x 10(6) M-1 or 40-fold that of unaffected relatives of 3.9 x 10(4) M-1. In contrast, the Ka of HSA for T4 in an affected subject was only 1.5-fold that of a normal. Albumin complementary DNA from leukocytes of affected member was amplified and sequenced. We found the second nucleotide of normal codon 66 (CTT), a thymine, was substituted by a cytosine (CCT), resulting in the replacement of the normal leucine by proline. This is the first report of variant albumin causing familial dysalbuminemic hypertriiodothyroninemia.

Mutation in the thyroid hormone receptor beta gene (A317T) in a Thai subject with resistance to thyroid hormone.

Analysis of the thyroid hormone receptor beta (TRbeta) gene of a Thai female with the syndrome of resistance to thyroid hormone (RTH) revealed a missense mutation at codon 317, changing the guanine in nucleotide 1234 to an adenine that results in the replacement of the normal alanine (GCT) with a threonine (ACT). The proposita was heterozygous, and this mutation was not present in her parents and her sister, compatible with a neomutation. This is the first report of TRbeta gene mutation causing RTH in an individual of Thai origin.

Thyroid function and human chorionic gonadotropin in patients with hydatidiform mole.

Sixty-seven patients with molar pregnancy were studied on admission to Rajvithi Hospital from 1992 to 1996. Thyroid function tests and serum hCG concentrations were measured. On the basis of thyroid function test results, the patients could be subdivided into three groups; Group I (hyperthyroid), Group II (subclinical hyperthyroid) and Group III (nontoxic). We found significant correlation between hCG and T4, T3 and FT4I levels (rho = 0.559, p < 0.001 n = 35; rho = 0.629, p < 0.001 n = 35; and rho = 0.465, p = 0.010 n = 30 respectively). These findings support that a variant hCG is responsible for hyperthyroidism observed in patients with molar pregnancy.

An identical neo-mutation in the thyroid hormone receptor beta gene (A317T) in 2 unrelated Thai families with resistance to thyroid hormone.

We reported two unrelated Thai girls with resistance to thyroid hormone. The affected patients presented with goiter and no other stigmata of hyperthyroidism. Their serum T4, T3, free T4 and free T3 concentrations were high and they had normal levels of TSH. The affected girl in family 1 was treated with an antithyroid drug for 1-9/12 years. The affected girl in family 2 was only observed her thyroid function tests. TRH test showed normal TSH response in both girls. Analysis of the thyroid hormone receptor beta gene of both affected girls revealed the same missense mutation, changing the guanine in nucleotide 1234 to an adenine which results in the replacement of the normal alanine (GCT) with a threonine (ACT) at codon 317. Two proposita were heterozygous, and this mutation was not present in their parents compatible with a neo-mutation.

A case of thyrotropin-secreting pituitary macroadenoma.

We present a 49 year old male patient with thyroid stimulating hormone (TSH) producing pituitary macroadenoma. He had been mistakenly diagnosed and treated as Graves' disease for 1 year. Serum TSH level was inappropriately elevated in the presence of high serum total and free thyroid hormone concentrations. Thyrotropin releasing hormone stimulation showed blunt response of TSH but good response for prolactin. The alpha-subunit level and alpha-subunit to TSH molar ratio were measured and found to be high before surgery. The sex hormone-binding globulin level was also high. MRI demonstrated a pituitary macroadenoma. Insulin tolerance test and GnRH revealed normal response. The patient was given a high dose of PTU combined with lugol's solution for controlling hyperthyroidism preoperatively. Transfrontal surgery was performed and the tumor was partially removed. The diagnosis was confirmed by tissue pathology and immunohistochemistry staining of the tumor. The immunohistochemistry staining was performed and found that tumor cells were strongly reactive to TSH with a relatively mild degree for follicular stimulating hormone and leutinizing hormone. The tumor cells were not stained for prolactin, growth hormone and ACTH. Supervoltage irradiation by 60Co was delivered to the pituitary area because of persistence of hyperthyroidism. While waiting for the remote effect of radiotherapy, the patient was given an antithyroid drug to control hyperthyroidism.

Simple and sensitive test for thyroid hormone autoantibodies.

We presented a simple and sensitive test for thyroid hormone autoantibodies. The normal range for T4 and T3 autoantibodies in Thai people considering mean +/- 3 S.D. were 1.8-9.4 per cent and 3.1-8.6 per cent, respectively. Although positive low titer of thyroid hormone autoantibodies had almost no interference of thyroid hormone levels, high titer might cause great interference. This method can be used for screening patients who have unexpectably high levels of serum T4, T3 or discrepancy between thyroid hormone levels and clinical findings.