The sequelae of untreated maternal hypothyroidism.

The concept that gestational subclinical hypothyroidism could have deleterious effects on the intellectual outcome of progeny was championed more than three decades ago by Evelyn Man in a series of publications. Her studies lay fallow until the Spanish group directed by Morreale de Escobar and the Dutch group headed by Vulsma provided the rationale for her results. Although the findings of the Spanish and Dutch groups elucidated the pathophysiologic basis for Man's conclusions, questions remained regarding the reliability of her biochemical measurements and possible bias in patient selection. In view of the uncertainty surrounding the validity of Man's work, we decided to try to confirm her findings. Our initial goal was to obtain an estimate of the prevalence of subclinical hypothyroidism in an unselected population living in New England. We accomplished this with two separate prospective studies involving 12 000 pregnant women residing in Maine. We found that 2.3% had TSH concentrations of >6.0 mU/l and 0.3% had TSH values of >12 mU/l at 17 weeks' gestation. We next did a retrospective study, utilizing sera that had been stored at -20 degrees C for 8 years, obtained in week 17 of gestation from 25 000 women. We identified 62 women with subclinical hypothyroidism and 124 matched controls. Fourteen of the hypothyroid mothers had been diagnosed and treated before and during pregnancy on a dosage of thyroxine that was unchanged. WISC IQs of the offspring of the 124 control and 62 hypothyroid mothers were determined at 8+/-0.5 years. The mean and s.d. of IQs of the children of the 124 control and of the 14 treated hypothyroid mothers were significantly higher than those of the children of the 48 untreated hypothyroid women. More than twice as many children of the untreated mothers had IQs of >1 s.d. below the control mean, and four times as many of the children had IQs 2 s.d. below the control mean, as did the children of the controls. A comparison of the mean hormonal values of the treated and untreated mothers at 17 weeks showed no significant difference in any of the biochemical markers. We surmise that the circulating level of thyroxine was normal in the treated mothers at a critical time before 17 weeks' gestation, but by 17 weeks it was insufficient to meet the growing demands of pregnancy. Treatment should begin as early as possible in pregnancy with the goal of maintaining free thyroxine (FT(4)) in the upper half of the normal reference range and TSH in the lower half of the normal reference range. In view of these data, we believe that all pregnant women should be screened for hypothyroidism as early in pregnancy as possible (or even before conception). To be cost-effective, screening programs should be based on those designed for congenital hypothyroidism, in which filter-paper blood specimens are forwarded to regional laboratories for thyroid function determinations.

Iodine sufficiency and measurements of thyroid function in maternal hypothyroidism.

OBJECTIVES: To test the hypothesis that thyroglobulin (Tg) and free T4 (FT4) concentrations more than 2SD from the control mean are not increased in pregnancy in an iodine replete area in the absence of elevated TSH concentrations. The second hypothesis to be tested was that if such abnormalities in FT4 and Tg in the absence of elevated TSH concentrations were to exist they would not be associated with lowered IQs in the progeny. DESIGN: Cross-sectional study in New England comparing TSH, Tg, antibodies to Tg and FT4 in volunteer nonpregnant women 20-40 years old with those in hypothyroid mothers and matched euthyroid control mothers. The results are contrasted with those from similar studies reported from iodine deficient areas. SUBJECTS: Sera obtained at 17 weeks gestation and stored at -20 degrees C for 8 years were retrieved and analysed from 62 mothers with subclinical hypothyroidism and 124 matched euthyroid mothers. The diagnosis of hypothyroidism was made by finding a TSH concentration > 97.7 percentiile for 25 000 consecutive pregnant women. Sera were also analysed from 53 healthy nonpregnant volunteer women aged 20-40 years. MEASUREMENTS: TSH, Tg and Tg antibodies were measured in the sera of the nonpregnant volunteers, and Tg and Tg antibodies in the sera of the pregnant women who had previously been analysed for TSH and FT4. The incidence of FT4 concentrations below the 2.3 percentile of nonpregnant laboratory controls was compared for the euthyroid and hypothyroid mothers and the laboratory normal controls. RESULTS: Thirty-one per cent of the 62 hypothyroid mothers had FT4 concentrations below the 2.3 percentile compared with only one (0.8%) of the euthyroid mothers. Mean Tg concentrations did not differ between the nonpregnant controls and the euthyroid pregnant women, 14 +/- 10 vs. 16 +/- 10 micro g/l. Tg concentration in the hypothyroid mothers was 44 +/- 61, significantly greater than for either of the euthyroid control groups, P < 0.005. Positive antibodies to Tg were found in 9% and 10% of the control groups and 57% of the hypothyroid mothers, P < 0.0005. When TSH is included as an independent variable in multiple linear and logistic regressions, FT4 and Tg no longer correlate significantly with IQs. CONCLUSIONS: The incidences of FT4 concentrations more than 2SD below the control mean and of Tg > 2SD above the control mean are significantly increased in hypothyroid mothers in iodlne-sufficient New England. However, in the absence of elevated TSH concentrations, the incidences of such abnormalities in FT4 and TG are negligible. Indeed, concentrations for FT4, Tg and Tg antibodies for nonpregnant and pregnant controls in our iodine-replete area do not differ significantly from each other or from previously reported normative concentrations with the methods used. Thus, pregnancy in New England neither increases Tg nor lowers FT4 concentrations.

Relation of severity of maternal hypothyroidism to cognitive development of offspring.

BACKGROUND: An association between maternal subclinical hypothyroidism and low intelligence quotient (IQ) in the offspring has recently been shown. OBJECTIVE: To provide evidence for the causality of the association by testing the hypothesis that severity of maternal hypothyroidism correlates inversely with IQ of the offspring. METHODS: IQ scores were compared among 8 year old offspring of 124 control mothers whose thyroid stimulating hormone (TSH) concentrations were < 98th percentile of a cohort of 25,000 mothers at 17 weeks gestation, of 28 untreated hypothyroid women whose TSH was between the 98th and 99.85th percentiles, and of 20 untreated women whose TSH concentration was > or = 99.85th percentile. RESULTS: Mean (SD) IQs for each group of children (in ascending order of maternal TSH concentration) were 107 (13), 102 (15), and 97 (14). The difference between the extremes was significant (p = 0.003). The percentage of children with IQs > 1 SD below the control mean was 15, 21, and 50 respectively (p = 0.003). The odds ratio of having an IQ > 1 SD below the control mean, after controlling for socioeconomic status, was 4.7 (p = 0.006) for the third group compared with the controls. CONCLUSIONS: The inverse correlation between severity of maternal hypothyroidism and IQ of the offspring supports a causal relation and makes the need to screen for and treat pregnant women for hypothyroidism even more compelling.

Maternal thyroid deficiency and pregnancy complications: implications for population screening.

OBJECTIVE: To examine the relation between certain pregnancy complications and thyroid stimulating hormone (TSH) measurements in a cohort of pregnant women. METHODS: TSH was measured in sera obtained from women during the second trimester as part of routine prenatal care. Information was then collected about vaginal bleeding, premature delivery, low birthweight, abruptio placentae, pregnancy induced hypertension, need for cesarean section, low Apgar scores, and fetal and neonatal death. RESULTS: Among 9403 women with singleton pregnancies, TSH measurements were 6 mU/l or greater in 209 (2.2%). The rate of fetal death was significantly higher in those pregnancies (3.8%) than in the women with TSH less than 6 mU/l (0.9%, odds ratio 4.4, 95% confidence interval 1.9-9.5). Other pregnancy complications did not occur more frequently. CONCLUSION: From the second trimester onward, the major adverse obstetrical outcome associated with raised TSH in the general population is an increased rate of fetal death. If thyroid replacement treatment avoided this problem this would be another reason to consider population screening.

The association between state housing policy and lead poisoning in children.

OBJECTIVES: This study examined the effect of an active program of household lead paint hazard abatement, applied over 22 years, on childhood lead poisoning in Massachusetts. METHODS: A small areas analysis was used to compare screening blood lead levels of children in Worcester County, Mass (n = 27,590), with those in Providence County, RI (n = 19,071). Data were collapsed according to census tract. RESULTS: The percentage of children with lead poisoning (blood lead level > or = 20 micrograms/dL [Pe20]) was, on average, 3 times higher in Providence County census tracts (3.2% vs 0.9% in Worcester County census tracts, P < .0001), despite similar percentages of pre-1950s housing in both counties. The ratio of Pe20 in Providence vs Worcester County census tracts was 2.2 (95% confidence interval = 1.8, 2.7), after adjustment for differences in housing, sociodemographic, and screening characteristics. This estimate was robust to alternative regression methods and sensitivity analyses. CONCLUSIONS: Massachusetts policy, which requires lead paint abatement of children's homes and places liability for lead paint poisoning on property owners, may have substantially reduced childhood lead poisoning in that state.

Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child.

BACKGROUND: When thyroid deficiency occurs simultaneously in a pregnant woman and her fetus, the child's neuropsychological development is adversely affected. Whether developmental problems occur when only the mother has hypothyroidism during pregnancy is not known. METHODS: In 1996 and 1997, we measured thyrotropin in stored serum samples collected from 25,216 pregnant women between January 1987 and March 1990. We then located 47 women with serum thyrotropin concentrations at or above the 99.7th percentile of the values for all the pregnant women, 15 women with values between the 98th and 99.6th percentiles, inclusive, in combination with low thyroxine levels, and 124 matched women with normal values. Their seven-to-nine-year-old children, none of whom had hypothyroidism as newborns, underwent 15 tests relating to intelligence, attention, language, reading ability, school performance, and visual-motor performance. RESULTS: The children of the 62 women with high serum thyrotropin concentrations performed slightly less well on all 15 tests. Their full-scale IQ scores on the Wechsler Intelligence Scale for Children, third edition, averaged 4 points lower than those of the children of the 124 matched control women (P= 0.06); 15 percent had scores of 85 or less, as compared with 5 percent of the matched control children. Of the 62 women with thyroid deficiency, 48 were not treated for the condition during the pregnancy under study. The full-scale IQ scores of their children averaged 7 points lower than those of the 124 matched control children (P=0.005); 19 percent had scores of 85 or less. Eleven years after the pregnancy under study, 64 percent of the untreated women and 4 percent of the matched control women had confirmed hypothyroidism. CONCLUSIONS: Undiagnosed hypothyroidism in pregnant women may adversely affect their fetuses; therefore, screening for thyroid deficiency during pregnancy may be warranted.

Randomized trial of calcium glycerophosphate-supplemented infant formula to prevent lead absorption.

BACKGROUND: Although additional dietary calcium is recommended frequently to reduce the risk of lead poisoning, its role in preventing lead absorption has not been evaluated clinically. OBJECTIVE: The objective was to determine the safety and to estimate the size of the effect of calcium- and phosphorus-supplemented infant formula in preventing lead absorption. DESIGN: One hundred three infants aged 3.5-6 mo were randomly assigned to receive iron-fortified infant formula (465 mg Ca and 317 mg P/L) or the same formula with added calcium glycerophosphate (1800 mg Ca and 1390 mg P/L) for 9 mo. RESULTS: There was no significant difference between groups in the mean ratio of urinary calcium to creatinine, serum calcium and phosphorus, or change in iron status (serum ferritin, total iron binding capacity). At month 4, the median (+/-SD) increase from baseline in blood lead concentration for the supplemented group was 57% of the increase for the control group (0.04 +/- 0.09 compared with 0.07 +/- 0.10 micromol/L; P = 0.039). This effect was attenuated during the latter half of the trial, with an overall median increase in blood lead concentration from baseline to month 9 of 0.12 +/- 0.13 micromol/L for the control group and 0.10 +/- 0.18 micromol/L for the supplemented group (P = 0.284). CONCLUSIONS: Supplementation did not have a measurable effect on urinary calcium excretion, calcium homeostasis, or iron status. The significant effect on blood lead concentrations during the first 4 mo was in the direction expected; however, because this was not sustained throughout the 9-mo period we cannot conclude that the calcium glycerophosphate supplement prevented lead absorption in this population.

Diagnostic testing unwarranted for children with blood lead 10 to 14 microg/dL.

BACKGROUND: Recent statements from the American Academy of Pediatrics and Centers for Disease Control and Prevention recommend diagnostic venous blood lead testing within 90 days of a marginally elevated screening test (10-14 microg/dL). OBJECTIVE: To evaluate the ability of a marginally elevated capillary (CScr) or venous (VScr) blood lead screening test to predict venous diagnostic (VPb) blood lead (taken within 90 days of the screening test) that would prompt environmental evaluation (>/=20 microg/dL). DESIGN: Population-based follow-up study comparing CScr and VScr with VPb drawn within 90 days of the screening sample. This study population was drawn from all children aged 0 to 4 years who were screened in Worcester County, Massachusetts, and Providence County, Rhode Island, with CScr and VScr during calendar year 1994. OUTCOME MEASURES: To evaluate predictive validity, CScr and VScr were correlated with VPb. CScr, VScr, and VPb results were then separated into the following categories: <10, 10 to 14, 15 to 19, and >/=20 microg/dL. CScr and VScr categories were cross-tabulated against VPb categories, and logistic regression analysis was used to evaluate categorical elevations of CScr and VScr as predictors of VPb >/=20 microg/dL. RESULTS: Of 31 904 children screened with CScr, 5450 (17.1%) were elevated and 1278 were followed up with VPb within 90 days. Of 14 623 children screened with VScr, 2979 (20.4%) were elevated and 614 were followed up with VPb within 90 days. CScr was only weakly correlated with VPb (r = 0.39), whereas VScr was more strongly correlated with VPb (r = 0.73). Compared with CScr <10 microg/dL, CScr in the 10 to 14 microg/dL range did not identify a higher percentage of children with VPb elevation in any category, and falsely misclassified as lead poisoned some 77% of children. Compared with VScr <10 microg/dL, VScr in the 10 to 14 microg/dL range identified higher percentages of children with VPb in the 10 to 19 microg/dL range but not with VPb >/=20 microg/dL, and falsely misclassified as lead poisoned 42% of children. Compared with screening tests <10 microg/dL, the odds of identifying a child with VPb >/=20 were no different from 1 for CScr of 10 to 14 microg/dL (adjusted odds ratio 1.4 [95% confidence interval 0.3, 6.6]), CScr of 15 to 19 microg/dL (3.2 [0.7, 15.7]), or VScr of 10 to 14 microg/dL (0.9 [0.3, 3.0]). CScr and VScr in the 15 to 19 microg/dL range were associated with significantly higher odds of having VPb >/=20 microg/dL when compared with screening tests <10 microg/dL. CONCLUSIONS: These data indicate that special diagnostic testing within 90 days for children with CScr and VScr in the 10 to 14 microg/dL range does not result in greater identification of VPb >/=20. Raising the set point for diagnostic testing to 15 microg/dL in this sample would eliminate the unnecessary follow-up of 5162 children, of whom 3360 were falsely misclassified as having undue lead exposure.

Thyroid function in very low birth weight infants.

OBJECTIVES: The purpose of this study was to test the hypothesis that low circulating thyroxine concentrations characteristic of very low birth weight (VLBW) neonates (< 1500 g) are the result of decreased protein binding of thyroid hormones and to elucidate the mechanism(s) responsible and possible significance thereof. DESIGN: Cross-sectional comparison of thyroid related measurements in cord blood specimens from VLBW infants and from full term infants. Longitudinal comparison in cord and 2- and 4-week blood specimens from VLBW infants. PATIENTS: Cord blood specimens were analysed from 47 VLBW and 45 full term infants weighing > or = 2500 g. Repeat analyses in venous bloods from 32 of the VLBW infants were analysed at 2 weeks of age and again at 4 weeks in 23. The first cohort of patients was studied in 1994 and comprised 28 VLBW and 24 full term infants (Cohort A). The studies were repeated in 1995-96 in 19 VLBW infants and 21 full term infants (Cohort B). MEASUREMENTS: T4, free T4 (FT4), T3, thyroxine binding globulin (TBG), and TSH were measured in cord blood and 2- and 4-week venous specimens from VLBW infants and in cord blood specimens of full term infants. Molar ratios of T4/TBG were calculated. RESULTS: (1) Cord blood TBG, T4 and T3 concentrations of VLBW infants were each 60% of those of term infants. TBG concentrations were 397 +/- 111 vs 680 +/- 172 nmol/l (P < 0.0005). T4 concentrations were 76 +/- 22 vs 139 +/- 26 nmol/l (P < 0.0005). FT4 concentrations were in the normal adult range in both neonatal groups. T4/TBG ratios did not differ between the neonatal groups but were significantly less than that of adults (P < 0.001). (2) TSH concentrations in VLBW infants at 2 and 4 weeks were less than 50% of cord blood values. At 2 weeks, TBG concentrations of VLBW infants were unchanged from cord blood concentrations but mean T4 concentration fell by 18% and T4/TBG ratios by 21% (P < 0.005). Mean FT4 rose by 78% (P < 0.02). The changes in mean T4 and FT4 were due largely to FT4 concentrations of 37-113 pmol/l and T4 concentrations of 13-48 nmol/l in 5 infants. These infants also had lower T4/TBG ratios and were smaller and more ill than the remainder of the cohort. The changes disappeared by 4 weeks in 3 of the 4 infants tested. CONCLUSIONS: Cord T4/TBG ratios are the same in very low birth weight and term infants and are significantly lower than in adult blood. These are more than compensated for in term infants by a 236% increase in thyroxine binding globulin concentrations. The lower thyroxine binding globulin concentrations in very low birth weight infants explain their much lower T4 concentrations. Cord FT4 concentrations of full term and very low birth weight infants are in the normal adult range. T4 concentrations are further depressed and free T4 concentrations elevated in the most ill very low birth weight infants at 2 weeks of age in a manner analogous to that of the 'sick euthyroid syndrome'.

Calcium and phosphorus supplementation of iron-fortified infant formula: no effect on iron status of healthy full-term infants.

One objective of this clinical trial was to determine whether calcium and phosphorus supplementation of infant formula affects the iron status of healthy full-term infants. One hundred three infants were randomly assigned to receive iron-fortified, cow milk-based infant formula (465 mg Ca and 317 mg P/L) or the same formula with added calcium glycerophosphate (1800 mg Ca and 1390 mg P/L) for 9 mo. Reported calcium intake for supplemented infants was about four times that of control infants, ranging from a mean of 1741 mg/d at baseline to 1563 mg/d at 9 mo. There was no difference by treatment group in mean or median change from baseline of serum ferritin, total-iron-binding capacity, erythrocyte protoporphyrin, or hematocrit at 4 and 9 mo after enrollment. Incidence of iron deficiency was similar for both groups and no infant developed iron deficiency anemia during the trial. This study indicates that the well-documented inhibitory effect of calcium and phosphorus on iron absorption is not clinically important in infants fed iron-fortified infant formula.

Thyroid function in very low birth weight infants: effects on neonatal hypothyroidism screening.

OBJECTIVES: To supply normative data for screening thyroxine (T4) and thyrotropin concentrations correlated with birth weight and age at screening of infants with birth weights ranging from 400 to 5500 gm, and to document the effects of screening of very low birth weight (VLBW) infants, because VLBW infants comprise 0.86% of surviving newborn infants and have very low total T4 concentrations with normal or elevated free T4 concentrations as a result of deficient protein binding of thyroid hormones. STUDY DESIGN: Both retrospective and prospective studies were used. We conducted retrospective analyses of screening of T4 and thyrotropin concentrations in 9,324 term, 18,946 low birth weight, and 3,450 VLBW infants in Massachusetts, and a prospective study of T4 and thyrotropin concentrations in 48 VLBW infants at 2 weeks of age. Forty of the infants also had hormone measurements at 4 weeks, 29 at 8 weeks of age, and 24 had analysis of cord blood samples. RESULTS: Median T4 concentrations for each weight group (in 250 gm increments) increased progressively and significantly up to 2500 gm. Of the surviving VLBW infants, 1.5% had screening T4 concentrations that were unmeasurably low (<3.9 nmol/L (0.3 microgram/dl)). The mean T4 concentration varied with age at screening, increasing from cord blood concentrations to a peak at 1 to 3 days of age and thereafter decreasing to a nadir at about 2 weeks in both low birth weight and VLBW infants. In VLBW infants the mean concentrations return to the level of 1 to 3 days by 4 to 8 weeks of age. The incidence of screening thyrotropin concentrations > or = 40 mU/L correlates inversely with weight. The incidence of early, transient hypothyroidism in VLBW infants defined by this thyrotropin concentration was eight times that in term infants. Two infants had late-onset, transient hypothyroidism at 2 and 7 weeks, respectively. CONCLUSIONS: The normative data related to birth weight and age at screening allow proper interpretation of VLBW results for primary T4 and primary thyrotropin screening programs. Screening of the concentrations of T4 and thyrotropin in VLBW increases the number of secondary measurements of T4 in a primary thyrotropin screening program and the number of secondary thyrotropin measurements in a primary T4 screening program by 6% and 9%, respectively. We recommend screening analyses for VLBW infants in the latter part of the first week of life and again at 2 and 4 to 6 weeks of age. This protocol would increase the number of screening analyses by 1.6%.

Normal values for random urinary calcium to creatinine ratios in infancy.

OBJECTIVE: To determine normal values for the urinary calcium/creatinine ratio (UCa/Cr) in infants. To assess the impact of short-term supplementation of infant formula with calcium and phosphorus on UCa/Cr in a group of infants. DESIGN: We determined UCa/Cr in randomly collected urine samples from a group of children and adults. Short-term supplementation of infant formula with calcium glycerophosphate was carried out in 21 infants, and UCa/Cr was monitored in a before-and-after trial. SETTING: A pediatric clinic at an academic center (infants and adults), and a day-care center (older children). PARTICIPANTS: A total of 103 infants between 5 days and 7 months of age, 40 infants between 8 and 17 months of age, 41 children between 18 months and 6 years, and 31 adults. RESULTS: The 95th percentiles for molar UCa/Cr for the different age groups were as follows: less than 7 months, 2.42 (0.86 mg/mg); 7 to 18 months, 1.69 (0.60 mg/mg); 19 months to 6 years, 1.18 (0.42 mg/mg); and adults, 0.61 (0.22 mg/mg). Regression analysis indicated a statistically significant decline in average UCa/Cr with age (R2 = 0.115, p < 0.0001 for log (UCa/Cr) vs log (age)). The geometric means for the two groups of infants were significantly greater than those of the older children and the adults (p < 0.05). Values for UCa/Cr in adults in our sample were comparable to those previously reported. We detected no significant changes in mean UCa/Cr during week-long periods of calcium supplementation of up to 1.8 gm of calcium and 1.39 gm of phosphorus per liter of formula. CONCLUSION: We conclude that normal values for UCa/Cr are much higher in infants than in older children and adults; UCa/Cr is age-related and declines gradually in the first several years of life, and short-term supplementation of infant formula with calcium glycerophosphate has minimal effect on UCa/Cr.

Prevalence of thyroid deficiency in pregnant women.

OBJECTIVE: The present study was designed to determine the current prevalence of gestational hypothyroidism, since maternal thyroxine deficiency is associated with poor obstetric outcomes and mental retardation in the surviving offspring. DESIGN: TSH concentrations were measured in the sera of women at 15-18 weeks of gestation. Those sera with TSH concentrations above 6 mU/l and the two sera closest in order with TSH concentrations below 6 mU/l were further analysed for T4, FT4, TBG, and antithyroid antibodies. Study criteria for hypothyroidism were sera with elevated concentrations of TSH plus both a free T4 concentration and a total T4 concentration and/or T4/TBG ratio more than two standard deviations below the mean for the control pregnant women. PATIENTS: The sera were from 2000 consecutive women in Maine being tested for alpha-fetoprotein concentration at 15-18 weeks of gestation. RESULTS: TSH concentrations above 6 mU/l were found in the sera of 49 women, 2.5% of the pregnant women. Six women with elevated TSH concentrations (range 6.9-54 mU/l) had both a FT4 concentration and a T4/TBG ratio and/or a T4 concentration more than two standard deviations below the respective control means, meeting the study criteria for thyroid deficiency, and thus giving a prevalence of 0.3%. The remaining 43 women with elevated TSH concentrations were classified as having compensated thyroid disease although some may have been hypothyroid. Fifty-eight per cent of women with TSH concentrations above 6 mU/l and 90% of the women with elevated TSH concentrations and at least one thyroxine index more than two standard deviations below the control means had positive titres of antithyroid antibodies as opposed to 11% of the controls. CONCLUSIONS: Although it is not known what severity of maternal thyroid deficiency is necessary to cause fetal brain damage, the present data indicate a sufficiently high prevalence of thyroid dysfunction to demand investigation of the mental development of the offspring of women with thyroid dysfunction and of the effect of replacement therapy.

A cluster of Pallister-Hall syndrome cases, (congenital hypothalamic hamartoblastoma syndrome).

We report on three infants with hand anomalies and congenital hypopituitarism. In two of the cases, a hypothalamic tumor was found; the third infant died without postmortem brain studies. Family history in the first case suggested possible familial recurrence; the mother's sister had died at 17 hr of age with polydactyly, microglossia, and flat nasal bridge (no autopsy done). Our second case was born by cesarean section after a pregnancy complicated by extremely low maternal estriols. At birth, hypopituitarism was diagnosed, a cranial CT scan was read as normal, and hormonal replacement was begun with thyroxine, hydrocortisone, and growth hormone. At 11.5 mo of age she developed seizures; and a repeat CT scan showed a mass extending beneath the hypothalamus. This tumor was removed surgically at 12 mo, the first successful treatment of this disorder. Our third possible case had a bifid epiglottis, hypopituitarism, and hand anomalies. A CT scan at birth failed to reveal a mass in the hypothalamus. This child died from complications of untreated hypopituitarism, and no neuropathology studies were done. These three cases were conceived between March 10th and April 17th in three different years in three geographically contiguous counties of Vermont. Clustering in time and space and possible familial recurrence, in one of these cases, suggest a possible gene/environment interaction.