Thomas P. Foley

Screening for congenital hypothyroidism: Results of screening one million North American infants

Pilot programs for screening of newborn infants for congenital hypothyroidism began in North America in 1972. To date, the five oldest programs (Quebec, Pittsburgh, Toronto, Oregon Regional, and New England Regional) have screened 1,046,362 infants. A total of 277 infants with congenital hypothyroidism have been detected and seven have been missed, resulting in a total of 284 affected infants in the screened population and an overall incidence of one in 3,684 live births. Of the affected infants, 246 were determined to have primary hypothyroidism, an incidence of one in 4,254 births. Ten infants with secondary-tertiary hypothyroidism were detected in Quebec, Oregon, and Toronto, an incidence of one in 68,200 births. Of all the infants with primary hypothyroidism who were adequately studied, 63% were determined to have aplastic or hypoplastic glands, 14% normal or enlarged glands, and 23% ectopic thyroid tissue. The estimated minimum incidence of infants with TBG deficiency is one in 8,913 births. Only 8 of the 277 detected infants were suspected clinically to have congenital hypothyroidism prior to the time of confirmation of the diagnosis at 4 to 8 weeks of age. The cost of screening varied from

Functioning thyroid masses in childhood and adolescence: Clinical, surgical, and pathologic correlations*

0.70 to

Neonatal thyroid function in congenital hypothyroidism

1.60 per infant, depending on which costs were included in the estimate. Preliminary evidence from Quebec suggests that infants treated in the program have normal developmental testing scores at 18 months of age.

Low somatomedin activity in cord serum from infants with intrauterine growth retardation

Six girls, aged 5 to 15 years, presented with thyroid masses in otherwise nonpalpable thyroid glands and with normal serum thyroxine levels. Scintiscanning before and after TSH stimulation confirmed the presence of autonomous nodules in the four adolescents, of whom two had elevated T3 levels. Surgical exploration revealed adenomatous thyroid hyperplasia in three of the girls and papillary adenocarcinoma in the fourth. Scans in the other two girls revealed absence of the left lobe. One of them proved to have agenesis of the left lobe with enlargement of the right lobe because of lymphocytic thyroiditis. The other girl had an ectopic thyroid with chronic inflammation. A thorough diagnostic evaluation of single or multiple functioning thyroid masses in children and adolescents is essential in establishing the correct diagnosis. The possibility that carcinoma can occur in autonomous nodules as well as in hemiagenesis and ectopic thyroid tissue is discussed. An approach to the management of functioning thyroid masses in the pediatric age group is proposed.

Prevalence of thyroid antibodies among healthy middle-aged women: Findings from the thyroid study in healthy women

In the cord blood of seven infants with congenital hypothyroidism detected in our newborn screening programs, thyroxine values ranged from 2.5 to 6.7 mug/dl and thyrotropin, from 105 to 975 muU/ml; triiodothyronine values were normal. On follow-up, T3 levels increased to normal in five infants, there was a significant negative correlation between the T3 value and the severity of thyroprevia as reflected in the TSH levels and the number of clinical features present. This increase in T3 may explain in part why the diagnosis of this disease is difficult during the first few months of life and why early treatment is effective. This observation provides further rationale for the widespread institution of newborn screening programs for congenital hypothyroidism.

1-Deamino-8-d-arginine vasopressin in the treatment of central diabetes insipidus in childhood*

Somatomedin activity was determined by the simultaneous incorporation of 35S-sulfate and 3H-methyl thymidine into costal cartilage from hypophysectomized rats in cord sera from term and preterm infants and infants with intrauterine growth retardation. Mean Sm activity by sulfate incorporation was 0.49 +/- 0.04, 0.35 +/- 0.05, and 0.09 +/- 0.03 units/ml (+/- SE) in the term, preterm, and IGR cord sera, respectively. The levels for each group were significantly different from each of the other groups. There was no significant difference between the mean Sm activity by thymidine incorporation in cord sera from term (0.92 +/- 0.09 units/ml) and preterm (0.87 +/- 0.08 units/ml) infants. These levels were significantly higher, however, than the Sm activity by sulfate incorporation for the respective groups, P less than 0.001 for both groups. The mean Sm activity by thymidine incorporation in cord sera for IGR infants was 0.36 +/- 0.13 units/ml, and significantly lower than the levels in cord sera of term and preterm infants (P less than 0.01). Inhibition of Sm activity by mixing cord serum and pooled adult serum was found in one of the two cord specimens tested from IGR infants. The low levels of Sm activity in cord sera from IGR infants may reflect altered intrauterine nutrition. The discrepancy in the thymidine and sulfate incorporation by the costal cartilage bioassay for term and preterm cord sera might result from Sm-like factors in human fetal serum with greater mitogenic or thymidine transport activity compared to the activity for proteoglycan synthesis in cartilage.

Rapid metabolic and newborn screening of thyroxine (T4) from dried blood spots by MS/MS.

Autoimmune thyroiditis is the most common cause of subclinical hypothyroidism in North America, is more common in women than men, and is a risk factor for the development of coronary heart disease (CHD). We measured thyroid-stimulating hormone (TSH) and two thyroid antibodies, thyroid peroxidase and thyroglobulin, in stored sera of the participants (aged 44 to 54 years) of the Healthy Women Study. We selected 254 samples from the premenopausal baseline examination in 1983 to 1985 and from a follow-up examination that occurred an average of 5.7 years later (range, 3 to 7.7 years). At follow-up, 95 women remained premenopausal, 98 had ceased menstruating for at least 12 months, and 61 were taking postmenopausal hormone therapy. Overall, the prevalence of the thyroid antibodies in this healthy population was high at both time points (21 to 26%). Women with antibodies had higher TSH concentrations than did those with no antibodies (2.68 +/- 1.3 versus 1.51 +/- .73 mU/L, P < 0.001); this relationship was statistically significant even after excluding those with subclinical hypothyroidism (TSH > 6.0 mU/L). TSH and antibody levels did not differ by menopausal status or hormone therapy use at follow-up. Given the high prevalence of thyroid antibodies among healthy middle-aged women, long-term follow-up is warranted to ascertain whether the presence of antibodies is associated with subsequent excess risk of disease, in particular, CHD.

Growth Hormone Releasing Hormone and Growth Hormone: Genetic Studies in Familial Growth Hormone Deficiency

The effectiveness of therapy with carbamazepine and clofibrate (oral therapy), intramuscular pitressin-in-oil, and intranasal 1-deamino-8-D-arginine vasopressin has been compared in 15 children with partial or complete central diabetes insipidus. Mean daily urine volume without therapy was 5.4 l and dropped to 1.1 and 1.6 l/day while receiving pitressin and DDAVP, respectively. Oral agents decreased the daily urine volume to 2.2 l in patients with partial DI, with good symptomatic control except for some nocturia. These agents had no effect in patients with complete DI and did not alter pitressin requirements. Duration of pitressin action was 24 to 36 hours with a significant incidence of hyponatremia. The duration of DDAVP effect was 8 to 20 hours, varying in individual patients. Children with partial DI required smaller doses of DDAVP and the duration of action was longer than in those with complete DI. Control of serum electrolytes was excellent using two doses per day and nocturia was eliminated. All patients who had received pitressin had growth hormone antibodies, but continued to grow normally unless there was pre-existing growth hormone deficiency. These antibodies gradually disappeared after approximately one year of therapy with oral agents or DDAVP. DDAVP did not alter growth hormone, cortisol, or prolactin levels during sleep. DDAVP is the antidiuretic therapy of choice in children with either complete or partial DI; to date, no side effects have been demonstrated.

Characterization of somatostatin specific binding in plasma cell membranes of human placenta.

BACKGROUND Thyroxin (T(4)) plays an important role in the regulation of the rate of metabolism of proteins, fats, and carbohydrates. Congenital hypothyroidism, an inherited deficiency of thyroid hormones, is screened in newborns using a variety of methods that include total T(4) or thyroid stimulating hormone (TSH). Some laboratories measure either total T(4) or TSH as a means of detecting infants with hypothyroidism with a subset that analyzes both total T(4) and TSH as a primary screen or a combination of primary and secondary screens. METHODS We have developed a new MS/MS method that measures T(4) from a filter paper blood spot following methanol extraction using the essentially the same method as MS/MS analysis of amino acids. Product ion spectra show a transition of 833.8-->731.8 (102 Da). An SRM for T(4) and (13)C(6)-T(4) was added to the MS/MS analysis of acylcarnitines and amino acids. RESULTS Analysis of T(4) by MS/MS compares well with the immunoassay. The mean of 10,225 newborn screening specimens was 14.4 microg/dl (range 2.4-33) for MS/MS and 16.9 microg/dl (range 1.4-71.8) for AutoDELFIA. The MS/MS assay was linear with a correlation coefficient of 0.998. Regression analysis of MS/MS with the AutoDELFIA had a slope of 0.7, a y-intercept of 3.25, and a correlation coefficient of 0.727. We determined a MS/MS detection limit of 0.97 microg/dl and a lower LoQ (limit of quantification) of 2 microg/dl. CONCLUSION This method may provide a cost effective means of analyzing both T(4) and TSH by consolidating a T(4) analysis into the MS/MS panel.

Type 1 diabetes in offspring of parents with type 1 diabetes: the tip of an autoimmune iceberg?

ABSTRACT: Four families with growth hormone (GH) deficiency, either isolated or with other pituitary hormonal deficits are described. Members of each underwent pharmacological testing for GH secretion and infusions of GH releasing hormone (GHRH) to determine the locus of the defect in GH secretion. In addition, we have extracted DNA from white blood cells to characterize the GHRH and GH genes. All members tested had the normal complement of GH and GHRH genes. Four generations of one family with isolated GH deficiency, autosomal dominant were studied. The younger members showed minimal GH responsiveness to a single infusion of GHRH. However, the older members did not respond even after 30 doses of GHRH given intravenously every 3 h. Two members of a family with the autosomal recessive type of isolated GH deficiency had large GH increases after GHRH infusion. Thus in these families the GH secretory defect lies within the hypothalamus. Members of two families with pituitary deficiency (GH and other tropic hormones) of the autosomal recessive type had variable responses to GHRH and varying amounts of pituitary tissue seen on high resolution CT scans. Although it is not possible to delineate the precise location of the secretory defects in these latter two families, a hypothalamic defect is probable based on the responses to multiple trophic stimuli. Heterogeneity of structure and function exists within and between families with isolated GH deficiency and within and among families with pituitary deficiency. It is from the study of such families in which all members presumably have the same underlying defect that one can more readily decide on a pathogenetic mechanism.