Serum thyroglobulin levels in preterm infants with and without respiratory distress syndrome. II. A longitudinal study during the first 3 weeks of life.

Serum thyroglobulin (Tg) and thyroid-stimulating hormone (TSH) levels were measured in 182 preterm and term infants. Samples were taken from cord blood, and at 1, 3, 7, 14, and 21 days after birth. The infants were divided into groups according to their perinatal characteristics: infants who were appropriate for gestational age, infants who were small for gestational age, and preterm infants who developed respiratory distress syndrome. These groups were subdivided according to gestation age. Tg serum levels showed a significant increase in the 1st day in all groups, and decreased significantly after about 1 wk. The highest Tg levels were found in the 1st wk of life in respiratory distress syndrome infants, and in infants with the lowest gestation ages. TSH levels increased at day 1 but only in appropriate and small for gestational age infants of more than 30 wk of gestation. TSH levels at day 1 in the groups with gestation ages of less than 30 wk and in respiratory distress syndrome infants of more than 30 wk were low, reflecting a low TSH surge. We conclude that the neonatal increase of Tg is not merely caused by the TSH surge. We suggest that the Tg increase is due to an impaired degradation of Tg, and/or to hemoconcentration, which are more pronounced in respiratory distress syndrome infants compared with appropriate for gestational age infants.

Serum thyroglobulin levels in preterm infants with and without the respiratory distress syndrome. I. Cord blood study.

Cord serum levels of thyroglobulin (Tg) and thyroid stimulating hormone (TSH) in 147 term and preterm infants were related to gestation age, birth weight, respiratory distress syndrome (RDS), and several perinatal factors by means of multiple linear regression analysis. None of the perinatal factors influenced Tg and TSH cord serum levels. However, in infants who developed RDS, Tg and TSH cord serum levels differed significantly from values in infants who did not develop this syndrome. In RDS infants, significantly higher Tg values were found. Tg cord serum levels increased with birth weight in the "average" RDS infant (i.e. infants with birth weights according to the 50th percentile of the growth chart for their gestation age), while these levels decreased in the "average" non-RDS infant. In RDS infants TSH cord serum levels increased with increasing birth weight, while these levels did not vary in non-RDS infants. Although Tg and TSH cord serum levels in RDS infants increased during gestation, no correlation between Tg and TSH cord serum levels could be demonstrated. There was no correlation between Tg and TSH cord serum levels in non-RDS infants. Since we found a clear correlation between Tg cord serum levels and gestation age, but no correlation between Tg and TSH cord serum levels, we suggest that other phenomena are responsible for the high Tg levels such as organ immaturity.

Activity of peroxisomal enzymes and intracellular distribution of catalase in Zellweger syndrome.

The activity of peroxisomal enzymes was studied in human liver and cultured human skin fibroblasts in relation to the finding (Goldfischer, S. et al. (1973) Science 182, 62-64) that morphologically distinct peroxisomes are not detectable in patients with the cerebro-hepato-renal (Zellweger) syndrome. In homogenates of liver from the patients, dihydroxyacetone phosphate acyltransferase, a membrane-bound peroxisomal enzyme, is deficient (Schutgens, R.B.H., et al. (1984) Biochem. Biophys. Res. Commun. 120, 179-184). In contrast, there is no deficiency of the soluble peroxisomal matrix enzymes catalase, L-alpha-hydroxyacid oxidase and E-aminoacid oxidase. Catalase is also not deficient in homogenates of cultured skin fibroblasts from the patients. The results of digitonin titration experiments showed that in control fibroblasts at least 70% of the catalase activity is present in subcellular particles distinct from mitochondria or lysosomes. In contrast, all of the catalase activity in fibroblasts from Zellweger patients is found in the same compartment as the cytosolic marker enzyme lactate dehydrogenase.

Deficiency of plasmalogens in the cerebro-hepato-renal (Zellweger) syndrome.

We have analyzed the phospholipid composition of various organs of patients with the cerebro-hepato-renal (Zellweger) syndrome. The phospholipid composition of tissues from controls and patients was very similar except for their plasmalogen contents. In controls about 50% of the phosphatidylethanolamine fraction of brain, heart, kidney and skeletal muscle and about 10% of that fraction in control liver tissue was found to consist of plasmalogen. In control heart muscle, but not in other control tissues about 25% of the phosphatidylcholine fraction consist of plasmalogens. In contrast, plasmalogens were nearly absent in the corresponding tissues of Zellweger patients. The amount of phosphatidylethanolamine plasmalogens in both erythrocytes and fibroblasts of Zellweger patients is lowered significantly compared to control erythrocytes and control fibroblasts respectively, although this reduction is not as dramatic as in brain, heart, kidney, skeletal muscle and liver of patients. Phosphatidylcholine-plasmalogens are only present in low amounts in both controls, heterozygotes and patients. In recent years considerable evidence has accumulated to show that peroxisomes are involved in cellular lipid metabolism. Notably, the key enzymes of ether lipid (plasmalogen) biosynthesis in rodents were recently found to be located in peroxisomes. Since electronmicroscopic studies have shown that peroxisomes are absent in liver and kidney of patients with the cerebro-hepato-renal syndrome, our results suggest that an inability to integrate these key enzymes in a functional peroxisome leads to a severe disturbance in plasmalogen biosynthesis. We propose that the multiple clinical and biochemical defects in Zellweger patients are secondary to a deficiency in peroxisomal function.

Concentration of plasma thyroglobulin and urinary excretion of iodinated material in the diagnosis of thyroid disorders in congenital hypothyroidism.

In this paper we describe methods for the early aetiological diagnosis of congenital hypothyroidism, using beside the classical T4, T3 and TSH plasma concentrations, four additional parameters in plasma and urine. The first one is thyroglobulin (Tg). In normal children of more than one year of age and in adults, 5-35 ng/ml plasma is found, in neonates 2-3 weeks old, this level is 10-250 ng/ml. In patients with a stimulated thyroid gland, as in primary congenital hypothyroidism, plasma Tg levels increase. High Tg values are found in iodine deficiency and in organification defects. In the absence of the thyroid gland plasma Tg is undetectable. Low to normal levels are found in cases with hypoplasia of the gland. In patients with a disturbed synthesis of Tg, resulting in Tg deficiency of the gland, plasma Tg levels vary from undetectable to normal. The PBI-T4 plasma difference, which is caused by circulating abnormal iodoproteins is the second parameter. The products of thyroidal breakdown processes of the abnormal iodoproteins are excreted in the urine and used as the third parameter. We found that the excretion of this low molecular weight iodinated material (LOMWIOM) was increased only in Tg-deficient patients. If the neonate is found to be hypothyroid, thyroid hormone substitution must be given immediately. Blood and urine sampling can be done just before or even directly after starting the therapy. The measurements extended with the determination of the total iodine excretion (fourth parameter) can be carried out within 1 week. With these additional methods it appeared to be possible to distinguish between several types of congenital hypothyroidism in neonates found by screening.

The human thyroglobulin gene contains two 15-17 kb introns near its 3'-end.

We have cloned overlapping segments of the human thyroglobulin gene from a genomic cosmid library. Restriction mapping and electron microscopy show that a region of 38 kb at or near the 3'-end of this gene encodes only 850 nucleotides or 10% of the messenger RNA (mRNA) sequence. The region contains five exons of 130-210 nucleotides, split by introns of 1 to 15-17 kb. This represents the lowest ratio of coding to non-coding DNA (2.2%) found thus far in any eukaryotic gene. Blot hybridization under non-stringent conditions shows the presence of only one copy of this gene in the human genome and the absence of other closely related sequences.

Cerebro-hepato-renal syndrome of Zellweger: clinical symptoms and relevant laboratory findings in 16 patients.

The clinical features of 16 patients suffering from cerebro-hepato-renal syndrome are presented. Five of these children lived beyond 2 years. Four of them are still alive. The increase of pipecolic acid in serum and cerebrospinal fluid (CSF), the abnormality of the bile acids and the increased excretion of p-OH-phenyl lactate were a consistent finding. The concentration of pipecolic acid in urine was not always distinctly elevated. A loading test with DL-pipecolic acid was always abnormal.

Serum thyroglobulin levels: the physiological decrease in infancy and the absence in athyroidism.

The cord serum thyroglobulin levels of 218 neonates are much higher than the levels after the first year of life and show a wide range. A relation exists between a shorter gestational age and increased thyroglobulin levels. The serum thyroglobulin levels decrease within a few months after birth, but throughout the first year of life, these levels are still higher than the normal values at later ages (5-35 ng/ml). IN 3 athyroid children, thyroglobulin is undetectable in serum.

Mild variant of argininosuccinic aciduria.

A 7 and one half-year-old boy with a massive excretion of argininosuccinic acid is described. He exhibited only moderate mental retardation, cerebellar ataxia and both abnormal hair and skin. Argininosuccinate lyase activity in the erythrocytes of his parents and his sister was in the range expected for heterozygotes. The patient was put on a low protein diet with arginine supplementation and improved clinically and biochemically on this regime. The variability of the phenotypic expression of argininosuccinate lyase deficiency is stressed.

Euthyroidism via iodide supplementation in hereditary congenital goiter with thyroglobulin deficiency.

We have studied hereditary congenital goiter in an inbred strain of goats. On a normal diet, the goats were hypothyroid and iodide taken up by the gland was released rapidly in the form of iodinated macromolecular material. This resulted in a low thyroidal iodine pool. An extremely low amount of thyroglobulin-related antigens (12 microgram/g tissue; normal, 100 mg/g tissue) was detected in the goitrous gland by RIA. Addition of 1 mg I-/day to the diet made the goats euthyroid and the serum protein-bound iodine increased to high values. Even under these conditions, however, the amount of thyroglobulin-related antigens was not significantly elevated (19 microgram/g tissue). On sucrose gradient, these antigens sedimented in the 7S region. No thyroglobulin-related antigens sedimented at 12S or 19S. Besides iodoalbumin, a heterogeneous group of abnormal iodoproteins containing T3 and T4 was observed with this high iodide intake and may have accounted for the hormone production. The abnormal iodoproteins had a molecular weight of 300,000-500,000 and a sedimentation value of about 7S. From these findings, we conclude that these goats were unable to synthesize thyroglobulin but with excess iodide, there was sufficient formation of T3 and T4 in the abnormal iodoproteins to make the animals euthyroid.

Hereditary congenital goiter with thyroglobulin deficiency in a breed of goats.

Hereditary congenital goiter occurring in an inbred breed of goats is reported. The goitrous goats were severely hypothyroid. Thyroglobulin-related antigens could only be detected by radioimmunoassay in amounts of 0.03% of the total protein concentration in the 105,000 x g supernate of the goitrous gland, which corresponded with 8 microgram soluble thyroglobulin-related antigens/g tissue. After treatment with digitonin, 4 microgram thyroglobulin-related antigens/g tissue could be extracted from the sediment. This means that the gland contained about 12 microgram thyroglobulin-related antigens/g tissue (normal about 100 mg/g). However, no thyroglobulin (19S) could be detected by ultracentrifugation experiments, immunodiffusion, or immunoelectrophoresis. Iodinated proteins with sedimentation constants of 3-9S were found. Among these iodinated macromolecular compounds, iodinated "albumin" and some non-hydrolysable iodinated material was found. These last mentioned components were also found in the blood, indicating a leakage from the gland. As described for comparable cases, these results indicate a defect in thyroglobulin synthesis or its regulation.

Aberrant origin of left pulmonary artery (vascular sling). Report of the clinical and anatomic features in three patients.

The clinical and anatomical findings in 3 patients with aberrant origin of the left pulmonary artery from the right pulmonary artery ("vascular sling") are presented. All 3 children symptoms of severe respiratory distress shortly after birth. In 2 children the correct diagnosis was suggested from the roentgenogram of the thorax, because of an indentation in the anterior wall of the esophagus. The diagnosis was further endorsed by selective angiography of the aberrant left pulmonary artery. The second patient is of particular interest, since the correct diagnosis was missed because of the presence of a multitude of associated anomalies. These included a tracheobronchial anomaly, a ventricular septal defect with a dilated pulmonary trunk, and a left-ward shift of the heart secondary to pulmonary emphysema on the right. Therefore, the indentation in the esophagus was absent, while the shift and rotation of the heart led to a misinterpretation of the exact course of the left pulmonary artery on the angiocardiogram. These cases are presented to reemphasize that "vascular sling", although rare, is indeed a serious cause of respiratory distress in infancy. Early recognition is of vital importance, since surgical repair of the vascular anomaly seems to be the only benificial procedure in these patients.