Neurodevelopmental outcomes in congenital hypothyroidism: comparison of initial T4 dose and time to reach target T4 and TSH.

OBJECTIVES: To compare neurodevelopmental outcomes in severe and moderate congenital hypothyroidism (CH) among 3 different initial L-thyroxine doses and to examine the effect of the time to thyroid function normalization on neurodevelopmental outcomes. STUDY DESIGN: Neurodevelopmental assessments of 31 subjects included the Mullen Scales of Early Learning, Wechsler Preschool and Primary Scale of Intelligence-Revised, Wechsler Intelligence Scale for Children, Wide-Range Achievement Test, and Child Behavioral Checklist. RESULTS: Subjects started on higher initial L-thyroxine doses (50 mug) had full-scale IQ scores 11 points higher than those started on lower (37.5 mug) initial doses. However, verbal IQ, performance IQ, and achievement scores did not differ among the 3 treatment cohorts. Subjects with moderate CH had higher full-scale IQ scores than subjects with severe CH, regardless of the initial treatment dose. Subjects who took longer than 2 weeks to normalize thyroid function had significantly lower cognitive, attention, and achievement scores than those who achieved normal thyroid function at 1 or 2 weeks of therapy. CONCLUSIONS: Initial L-thyroxine dose and faster time to normalization of thyroid function are important to optimal neurodevelopmental outcome. In severe CH, it is important to choose an initial dose at the higher end of the recommended range to achieve these goals.

Follow-up of newborns with low thyroxine and nonelevated thyroid-stimulating hormone-screening concentrations: results of the 20-year experience in the Northwest Regional Newborn Screening Program.

OBJECTIVES: To determine the type and frequency of thyroid disorders detected in infants with low thyroxine (T4) and nonelevated thyroid-stimulating hormone (TSH) screening test results in the Northwest Regional Newborn Screening Program (NWRNSP) over the 20-year period from May 1975 to May 1995 and to determine the effect of follow-up of these infants on the overall recall rate. STUDY DESIGN: The NWRNSP requests a serum specimen in infants with an absolute T4 level < 38.6 nmol/L (< 3 mg/dl) and in infants with two filter paper T4 concentrations less than the 3%, regardless of the TSH concentration. We conducted a retrospective analysis of infants who were followed up because of low T4 and nonelevated TSH concentrations on newborn screening. To determine the effect of follow-up of infants with low T4 levels, nonelevated TSH concentrations on the recall rate, we selected 1 year (1994) for review. Serum sample requests were evaluated to determine the reason for the request. RESULTS: Over this 20-year period, the NWRNSP detected 450 infants with primary hypothyroidism among 1,747,805 infants screened (1:3,884). Of these, 416 were detected on the basis of low T4 levels and nonelevated TSH screening test results, whereas an additional 34 infants with primary hypothyroidism and 29 infants with hypopituitary hypothyroidism were detected as a result of follow-up of low T4 levels and nonelevated TSH screening test results. This included 25 infants with delayed TSH rise (1:67,226), 9 infants with mild hypothyroidism (TSH levels < 25 mU/L) (1:194,212), 29 infants with hypopituitary hypothyroidism (1:60,269), and 434 infants with T4-binding globulin deficiency (1:4,027). Excluding those with T4-binding globulin deficiency, the false-positive rate was 43.5:1. This compares with an overall false-positive rate of 12:1 for our screening program. CONCLUSION: Follow-up of infants with low T4 and nonelevated TSH concentration on screening led to the detection of 63 additional infants with hypothyroidism, for an overall frequency of 1:27,743. We believe this yield justifies continued follow-up of infants with low T4 levels, nonelevated (TSH) screening test results in our program.

Variability of plasma cortisol levels in extremely low birth weight infants.

Cortisol is secreted by children and adults in a pulsatile pattern of 15-30 peaks and nadirs each day with a circadian rhythm. Newborns are known to lack the circadian pattern, leading to uncertainty about the appropriate time for blood sampling for assessment of adrenal function. Because extremely low birth weight (ELBW) infants may manifest signs of adrenal insufficiency, knowledge of the pattern of cortisol levels is necessary to guide the appropriate timing of blood sampling. To define the pattern of plasma cortisol levels in 14 ELBW infants, we obtained blood specimens every 20 min over a 6-h period at 4-6 days of life. Although cortisol levels in the 14 infants ranged from 2.0-54.5 micrograms/dL, each infant's cortisol levels varied little from his or her own mean cortisol level. The SDs calculated from each infant's mean cortisol level were small, ranging from 0.37-4.12 micrograms/dL. Cluster analysis was applied to the data; only 0.6 cortisol pulses/infant 6-h period were detected. Each infant's plasma cortisol levels were plotted against time, and regression analysis was performed. The slopes of the resulting lines of regression ranged from -0.0284 to 0.0221. Our data indicate that ELBW infants show little variability in their plasma cortisol levels over time; therefore, a single random measurement provides an adequate reflection of the adrenal status of the ELBW infant.

Corticosteroid binding globulin, total serum cortisol, and stress in extremely low-birth-weight infants.

Our objective was to determine if low levels of corticosteroid binding globulin (CBG) might explain the low serum total cortisol levels found in some extremely low-birth-weight (ELBW) infants. In a prospective study, serum total cortisol and CBG were measured in single blood samples from 31 ELBW infants, with a gestational age less than 28 weeks, in the first 8 days of life. Severity of illness was assessed using the Score for Neonatal Acute Physiology Perinatal Extension (SNAP-PE). The mean serum total cortisol (mean +/- 1 SD) was 9.2 +/- 9.8 mcg/mL and the mean CBG level was 1.4 +/- 0.31 mg/dL. There was no significant correlation between serum total cortisol and CBG levels (r = -0.18), severity of illness as measured by the SNAP-PE (r = +0.12), or birth weight (r = -0.12). Five of 31 infants, having a mean SNAP-PE score of 41, had serum total cortisol levels < or = 3.0 mcg/dL. Estimated mean serum free cortisol concentrations in these five infants (0.76 mcg/dL) were comparable to estimated free cortisol levels diagnostic of adrenal insufficiency in sick adult patients. Our findings indicate that CBG levels are lower in ELBW infants than in term infants, but low CBG levels do not explain the low serum total cortisol levels found in some very sick infants. Low cortisol levels in small premature infants may be adequate to support growth if the infant is well, but may result in a syndrome of adrenal insufficiency in those with severe illnesses.

Hypothalamic pituitary adrenal function in the extremely low birth weight infant.

Extremely premature infants manifest clinical features suggestive of adrenal insufficiency. Yet, serum cortisol levels are similar in ill and well preterm infants in a setting where one would expect high stress levels in the ill infants. We investigated the hypothalamic-pituitary-adrenal axis in 17 extremely low birth weight stressed premature infants, mean birth weight 739 g, gestational age, 26.1 weeks, using ovine CRH (oCRH) and ACTH stimulation. oCRH (1 microgram/kg) was administered at 2-7 days of life (mean = 4.1). ACTH rose from a basal value 6.0 +/- 0.8 pmol/L (mean +/- SEM) to 9.6 +/- 1.8 pmol/L (P < 0.01) at 15 min and 9.5 +/- 1.7 pmol/L (P < 0.01) at 60 min. Basal cortisol rose from 349.3 +/- 58.1 nmol/L to 422.3 +/- 57.9 nmol/L (P < 0.01) at 15 min and 568.7 +/- 60.2 nmol/L (P < 0.01) at 60 min. Cortisol values remained significantly (P < 0.05) elevated 24 h after oCRH. An ACTH stimulation test performed 24 h after the oCRH test demonstrated a significant cortisol rise from 603.5 +/- 130.5 nmol/L to 882.7 +/- 136.6 nmol/L (P < 0.05) at 60 min. Plasma CRH immunoactivity was also measured before oCRH testing and was detectable in 10 of 15 infants. The mean CRH immunoactivity was 21.8 +/- 4.4 pmol/L in the infants, significantly higher than 8 adult male controls (P < 0.04). Our results show a normal pituitary response to ovine CRH and a normal adrenal response to ACTH. We hypothesize that cortisol levels are inappropriately low in some ill preterm infants because of the inability of the extremely premature brain to recognize the stress of the illness or because of inadequate hypothalamic secretion of CRH. The significance of the measurable plasma CRH in the first week of life is unknown.

Massive levothyroxine ingestion. Conservative management.

The clinical course of a 29-month-old girl who was referred for evaluation after ingesting ninety 0.2-mg tablets of levothyroxine is reported. Despite an initial thyroxine (T4) level of 282 micrograms/dl and a triiodothyronine (T3) level of 1,837 ng/dl at 48 hours postingestion, her symptoms were mild and included irritability, vomiting, tremor, and tachycardia. Treatment was limited to activated charcoal and propranolol. Thyroid hormone levels fell to normal by 13 days postingestion. The child's clinical course was benign. Even after massive acute ingestions of levothyroxine, children's symptoms are usually mild and may be controlled with propranolol. This conservative approach should be considered before expensive and potentially dangerous therapies are undertaken.

Puberty in the syndrome of septo-optic dysplasia.

To determine the patterns of puberty associated with the syndrome of septo-optic dysplasia, 13 older children with optic nerve hypoplasia and hypopituitarism were studied. Three patterns of puberty were observed: early, rapidly progressive puberty (group 1); appropriately timed puberty (group 2); and delayed puberty associated with gonadotropin deficiency (group 3). In the six patients in group 1, puberty began at an early bone age. Pubertal changes progressed rapidly and the bone age advanced faster than chronologic time so that, despite a normal to increased growth rate, growth potential was lost. Group 2 comprised three patients with multiple pituitary hormone deficiencies but without gonadotropin deficiency who had the timing and progression of puberty expected in hypopituitarism. The four patients in group 3, all with multiple pituitary hormone deficiencies, had gonadotropin deficiency requiring sex steroid replacement.

Detection of congenital hypopituitary hypothyroidism: ten-year experience in the Northwest Regional Screening Program.

We examined the results of the Northwest Regional Screening Program (NWRSP) over its first 10 years to determine whether the detection of hypopituitary hypothyroidism is a justified advantage of the primary thyroxine (T4)-supplemental thyroid-stimulating hormone (TSH) screening strategy, and to determine whether all such infants will be detected by this screening approach. Between May 1975 and May 1985, the NWRSP screened 850,431 infants, detecting 192 infants with primary hypothyroidism (1:4429) and eight with hypopituitary hypothyroidism (1:106,304). In 11 additional infants, TSH deficiency, not detected by the screening program, was diagnosed on recognition of clinical features over the same period. Thyroid hormone treatment was begun in seven of the 11 infants prior to obtaining the screening sample results because of clinical symptoms of hypopituitarism, including hypoglycemia, persistent jaundice, microgenitalia, diabetes insipidus, midface hypoplasia, cleft lip or palate, or abnormalities of vision. The other four infants were not detected despite clinical features of hypopituitarism (in retrospect) and low serum T4 with TSH concentration below assay sensitivity on at least one screening sample. The most accurate assessment of total cases comes from Oregon, where all cases of congenital hypopituitarism are referred to our center; we estimate a frequency of 1:29,000. In our experience, a combination of newborn T4-supplemental TSH screening measurements and recognition of clinical features of hypopituitarism is the optimal strategy for detecting infants with congenital hypopituitary hypothyroidism.

Screening for congenital hypothyroidism with specimen collection at two time periods: results of the Northwest Regional Screening Program.

To determine the benefit of collecting two routine specimens to test for congenital hypothyroidism, we examined the results of our newborn screening program during the last 9.5 years. The Northwest Regional Screening Program (NWRSP) performs a primary thyroxine test with thyroid-stimulating hormone determinations on the lowest 10% of dried blood filter paper specimens. An initial specimen is obtained in the newborn period, and a routine second specimen is collected at approximately 4 to 6 weeks of age in all infants born in Oregon and 25% of infants born in Idaho, Montana, Alaska, and Nevada. Between May 1975 and October 1984, 182 infants with primary hypothyroidism were detected from 811,917 infants screened, a prevalence rate of 1:4,461. The routine second specimen led to the diagnosis of 19 infants of 484,604 infants screened, a detection rate of 1:25,505. When infants detected by the second screen were compared with those detected by the first screen, they had higher thyroxine and lower thyroid-stimulating hormone concentrations on filter paper and serum specimens. When thyroid scanning was used, all but one infant detected by the second screen had some residual thyroid tissue, whereas 35% of infants detected by the first screen had thyroid aplasia. Skeletal maturation was more likely to be normal in infants detected by the second screen. These infants appear to have milder hypothyroidism due to a later age of onset or slower evolution of thyroid failure. At a cost of $31,881 per infant detected by the second screen, the NWRSP found it cost-effective to obtain a routine second specimen.

Evolving hypopituitarism in children with central nervous system lesions.

At the time children with suspected hypopituitarism are seen with a subnormal growth rate, it is expected that testing will demonstrate growth hormone (hGH) deficiency. Seven patients with organic CNS lesions--three with histiocytosis X, one with septo-optic dysplasia, one with neonatal meningitis, one with an anterior encephalocele and meningitis, and one with neurofibromatosis who had normal growth hormone concentrations (greater than 7 ng/mL) despite a subnormal growth rate--were studied. Subsequent retesting 0.5 to 4.6 years later demonstrated the development of growth hormone deficiency. Four of the patients had evidence of other pituitary hormone deficiencies at the time of initial testing whereas two subsequently developed other deficiencies. The initial subnormal growth rate in these children may be secondary to their organic CNS lesion or an evolving hypopituitarism, perhaps with deficient somatomedin generation. These studies point out the need for continued observation and retesting in such patients.

Sexual precocity with hypothalamic hypopituitarism.

Two girls, one with septo-optic dysplasia and the other with posttraumatic brain damage, had the unusual combination of human growth hormone, thyrotropin, adrenocorticotrophic hormone, and vasopressin deficiencies that were associated with sexual precocity in one patient and early sexual maturation in the second patient, and of adult follicle-stimulating hormone and luteinizing hormone concentrations. At autopsy, the first patient had optic nerve aplasia, a normal pituitary gland, and some disorganization of myelinated fibers in the hypothalamus. The second patient had a normal thyrotropin and prolactin response to thyrotropin-releasing hormone, plus hyperphagia, deranged thirst mechanism, and temperature instability. These findings suggest that the lesion may be a defective hypothalamic regulation of pituitary hormone secretion. Congenital or traumatic hypothalamic-pituitary lesions may not affect all releasing factors or trophic hormones in a similar fashion.

Neonatal hypothyroidism detected by the Northwest Regional Screening Program.

The Northwest Regional Screening Program to detect congenital hypothyroidism in infants born in Oregon, Montana, Alaska, and Idaho (combined birthrate of 69,000/ yr) was added to our ongoing screening program in 1975. The program utilizes dried blood filter paper specimens collected routinely in the first few days of life in all four states and again at about 6 weeks of age in Oregon only. The screening test consist of an initial thyroxine (T4) measurement; a thyroid-stimulating hormore (TSH) determination is performed on those specimens with T4 concentrations in the lowest 3% group. Serum samples obtained by venipuncture are requested for confirmation of the diagnosis. In the first two years of the program, 25 infants with primary hypothyroidism were detected amont 110,667 infants screened, a frequency of 1:4,430. Fourteen cases of thyroxine-binding globulin deficiency were also detected, a frequency of 1:7,900. Using the T4 followed by TSH testing approach, the frequency of request for repeat specimens was 0.4% in Oregon and 0.05% in the other states. The cost per specimen was $1.96. The majority of infants lacked clinical signs or symptoms of hypothyroidism; only one infant was clinically suspected of having hypothyroidism prior to detection. The most common neonatal symptoms were constipation, lethargy, and prolonged jaundice, while the most common physical signs were hypotonia, umbilical hernia, and large fontanels. Thyroid scans showed the most common etiology to be thyroid aplasia, followed by an ectopic gland, hypoplasia, and goiter. Serum T4 concentrations were lowest in those infants with aplasia, intermediate in infants with an ectopic gland or hypoplasia, and normal in the infant with the goiter. Neonatal hypothyroidism varies in degree and has several different causes; the capacity to secrete thyroid hormone, the duration before hypothyroidism becomes clinically manifest, and possibly the eventual prognosis for intellectual function depend on the nature of the underlying cause. While the mean age at treatment was 59 days, the goal of diagnosing congenital hypothyroidism and treating affected infants by 1 month of age seems realistic.

Pubertal gynecomastia and transient elevation of serum estradiol level.

Serum levels of testosterone, estradiol, progesterone, 17alpha-hydroxyprogesterone, follicle-stimulating hormone, and luteinizing hormone were measured in 16 boys with pubertal gynecomastia. Six patients had elevated serum estradiol concentrations, and four of these six also had elevated progesterone levels. Serum estradiol/testosterone ratios were high for the stage of puberty in 11 of the 16 patients. In five patients who had two or more determinations, the steroid concentrations returned toward or into the normal range. Transient increases in serum estradiol concentration or an abnormally high estradiol/testosterone ratio may be causally related to the development of gynecomastia in adolescent boys.

Reversible hypothyroidism in growth hormone-deficient children treated with human growth hormone.

Six children with human growth hormone (hGH) deficiency became hypothyroid during the course of their therapy with hGH. This was accompanied by a decreasing growth rate, clinical symptoms of hypothyroidism and decreased serum T4 concentrations. Three of the 6 patients returned to the euthyroid state, both clinically and biochemically, with cessation of hGH therapy, and reinstitution of hGH precipitated hypothyroidism again in 2 of the three. The patients who remained hypothyroid have evidence of multiple pituitary trophic hormone deficiencies while those who reverted to euthyroidism appear to have isolated hGH deficiency. Evaluation of thyroid function while on hGH showed low T4, free T4 and T3 concentrations. The serum thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) was absent or markedly blunted in 4 of 6 patients while receiving long-term hGH therapy but was normal or exaggerated in all patients when tested before or after only 5 days of hGH therapy. These data indicate that exogenous hGH results in an inhibition of the TSH response to TRH. The mechanism of this inhibition is unclear, but we postulate that it may be mediated by somatostatin secretion in response to pulse doses of hGH.