Cheryl E. Hanna

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.

Androgen replacement in adolescents and young women with hypopituitarism.

The aim of this study was to test the hypothesis that young women with androgen deficiency due to hypopituitarism would benefit from androgen replacement in the form of dehydroepiandrosterone (DHEA). Five young women, age 15.2-23.1 years, with panhypopituitarism were studied in a 12-month double blind placebo-controlled crossover trial of DHEA replacement in a dose 50 mg/day (Belmar Pharmacy, Lakewood, CO). All had growth hormone (GH), thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH) and antidiuretic hormone deficiencies. Gonadotropin deficiency was complete in three and partial in two. The patients were evaluated at baseline, 6 months and 12 months. Serum hormone levels, body composition, lumbar bone mineral density (BMD), exercise capacity and tests of psychological function were performed. DHEA replacement restored serum DHEA levels to normal, 359.8+/-337 ng/dl (12.5+/-11.7 nmol/l). The Life Situation Survey showed significantly better life satisfaction on DHEA than placebo (110 vs 102, p = 0.05). Trends for improved maximal oxygen uptake (VO2), and decreased percent body fat did not reach statistical significance. In conclusion, androgen replacement with DHEA should be considered in young women with panhypopituitarism. Further studies over longer periods in larger groups of patients are necessary to better evaluate the effects of DHEA replacement on BMD, muscle strength and body composition.

Thyroxine-binding globulin deficiencydetected by newborn screening

We examined the results of the Northwest Regional Screening Program from May 1975 to June 1991 to determine the prevalence of inherited thyroxine-binding globulin (TBG) deficiency and its effect on thyroid hormone concentrations in infants. Serum thyroxine (T4), triiodothyronine resin uptake (T3RU), and thyrotropin values were requested of physicians caring for all infants with a single filter paper T4 level < 38.6 nmol/L (3 micrograms/dl) or a T4 level < 3rd percentile on two filter paper tests (at birth and 2 to 6 weeks of age). From 1,367,724 infants screened in five states, TBG deficiency, an X-linked disorder, was identified in 317 infants (285 boys). For the entire screening program the calculated frequency of TBG deficiency was 1:4315 infants (1:2400 for boys). In Oregon, where 95% of infants have two screening tests performed, the calculated frequency was somewhat higher (1:3080 infants; 1712 boys) and is probably more accurate. The mean serum T4 concentration for TBG-deficient boys was 41.9 nmol/L (3.26 micrograms/dl); 31% had values < 25.7 nmol/L (2.0 micrograms/dl). The mean serum T4 concentration for TBG-deficient girls was 60.2 nmol/L (4.68 micrograms/dl), with none < 2.0 micrograms/dl. The mean T3RU value was 0.472 in TBG-deficient boys, and 0.412 in TBG-deficient girls; the T3RU value was > 0.55 in 24% of TBG-deficient boys but was > 0.55 in only one girl. Free serum T4 levels were normal in all 56 TBG-deficient infants studied, and TBG levels were low in all 20 infants studied. Inherited TBG deficiency is common in boys in the Northwest, with a frequency of 1:1700 and a male/female ratio of 8.9:1. Boys with TBG deficiency have mild, moderate, or severe alterations in total T4 and T3RU values, but severe deficiency is rare in girls.

Metabolic evaluation of obese and nonobese siblings

OBJECTIVE To test the hypotheses that obese adolescents have a lower resting metabolic rate and less aerobic endurance than their nonobese siblings. DESIGN Case-referent study of obese and nonobese siblings from the same kindred. SETTING Tertiary referral center. PARTICIPANTS Telephone screening of community volunteers resulted in a consecutive sample of 16 kindreds. Obese and nonobese siblings were similar in age, height, and pubertal status. Significantly more female subjects were in the obese group (p less than 0.01). MEASUREMENTS AND MAIN RESULTS Body composition studies revealed that the obese siblings had higher body fat (p less than 0.001) but that fat-free mass was similar to that of the lean siblings. Resting metabolic rates determined by indirect calorimetry for the obese and nonobese pairs did not differ. Although the obese siblings appeared less fit when maximal oxygen consumption was measured in relation to total weight, maximal oxygen consumption did not differ when values were standardized for fat-free mass. CONCLUSIONS The obese adolescents did not have a reduced resting metabolic rate. As in adults, the relationship between resting metabolic rate and fat-free mass was similar for obese and nonobese children and adolescents. Any decreased sport participation by the obese siblings was not due to inherent reductions in aerobic capacity.

Effect of growth hormone replacement on development of hypothyroidism and hyperlipidemia

To determine the frequency with which hypothyroidism develops during human growth hormone therapy and to corroborate its onset with blood lipid changes, we measured growth rate, serum T4 and T3, and plasma cholesterol, triglyceride, and lipoprotein concentrations at 4-month intervals for a year in two subgroups of hGH-deficient children. The first group was initially euthyroxinemic (n = 16), and the second was TSH deficient and therefore already receiving thyroxine (n = 15). Basal plasma concentrations of total and low-density lipoprotein cholesterol and, to a lesser extent, plasma triglycerides were increased in both groups compared with an age-matched reference group. Basal plasma cholesterol levels were not statistically different in the euthyroxinemic and thyroxine-treated subgroups, and hGH treatment for a year did not lower lipid values in either subgroup. With hGH replacement, 25% of the euthyroxinemic patients experienced a slowdown in growth rate (3.2 +/- 0.7 cm/yr) associated with decreasing T4 (4.8 +/- 1.1 micrograms/dl) and increasing cholesterol concentrations (218 +/- 23 mg/dl); with thyroxine treatment, the growth rate improved (6.9 +/- 2.2 cm/yr), T4 increased (10.0 +/- 4.0 micrograms/dl), and cholesterol decreased (173 +/- 44 mg/dl, P less than 0.05). Although our results do not justify routine thyroid replacement, they do indicate that hypothyroxinemia and hypercholesterolemia may precede the growth slowdown during hGH treatment, and the need to monitor thyroid function at this time.

Reversible cardiomyopathy in an infant with unrecognized congenital adrenal hyperplasia.

We describe an infant who had a dilated cardiomyopathy and who was later found to have congenital adrenal hyperplasia. The cardiomyopathy resolved after replacement of glucocorticoid and mineralocorticoid. We believe that glucocorticoid deficiency may have played a direct role in the evolution of this cardiomyopathy.

Diminished thyroid-stimulating hormone secretion associated with neonatal thyrotoxicosis

lobacter may stimulate their production/ Alternatively, Campylobacter antibodies that penetrate the C S F may be responsible for neural damage. Kaldor and Speed have shown that patients with Guillain-Barr6 syndrome associated with Campylobacter gastroenteritis are more likely to have elevated C S F IgG titers than are similar patients with no history of Campylobacter infection. Another possibility is that the choleralike enterotoxin produced by C. jejum ~ may bind to neural tissue in a similar way to cholera toxin, causing neural damage. I~ Erythromycin therapy was not used initially because the child had made an uneventful recovery from her original illness. It was introduced later in her illness when she developed a febrile illness with exacerbation of diarrhea and was known to be still excreting Campylobacter. There is no evidence to suggest that erradication of the organism limits or prevents the neurologic syndrome2.5 We believe pediatricians should be more aware of the Campylobacter-Guillain-Barr6 syndrome association and that in patients with Guillain-Barr6 syndrome, particularly when associated with a gastrointestinal tract illness, C. jejuni should be sought as a possible etiologic agent.

Neonatal hypopituitary hypothyroidism associated with maternal thyrotoxicosis

Hypopituitary hypothyroidism was found in an infant born to a mother with inadequately treated thyrotoxicosis. The infant had low thyroxine (T4), low free T4, and diminished thyroid-stimulating hormone (TSH) levels with a blunted response to thyrotropinreleasing hormone (TRH) stimulation until 6 weeks of age when thyroid hormone replacement was started. Excess fetal thyroid hormone may have caused an alteration in TSH secretory dynamics leading to the development of neonatal hypopituitary hypothyroidism.

Primary hypothyroidism, empty sella, and hypopituitarism

Primary hypothyroidism may be associated with enlargement of the sella turcica, thought to represent hypertrophy and hyperplasia of the pituitary gland in response to lack of negative feedback of thyroid hormones) Thyroid ablation in mice and rats produces a progressive sequence of pituitary hyperplasia, enlargement, nodularity, and adenoma, which can be prevented by thyroid hormone treatment. 2 Subtle visual field defects resulting from pituitary enlargement have been documented in a majority of patients with primary hypothyroidism3; severe visual field loss and blindness have also been reported. 4s These changes may be reversible with thyroid hormone replacement: although in some cases craniotomy has been necessary.4,5 As might be expected, pituitary hormone alterations have also been documented in primary hypothyroidism, 7 and hypopituitarism, both transient 8 and permanent: has been reported. An empty sella is a reported outcome in some of these patients) ~ H We report an l 1-year-old boy with primary hypothyroidism associated with enlargement of the sella and pituitary gland, in whom an empty sella and hypopituitarism developed after thyroid hormone treatment. To our knowledge, this is the first child reported with this sequence of changes documented by CT scan

424 THE CLINICAL SPECTRUM OP OPTIC NERVE HYPOPLASIA, HYPOPITUITARISM, AND ABSENT SEPTUM PELLUCIDUM

Of 17 patients with optic nerve hypoplasia, hypopituitarism (HP), or absent septum pellucidum (SP), 11 presented with features of HP, 5 with eye signs, and 1 with microcephaly. Of the 11 with signs of HP, 9 had neonatal problems: 7 with hypoglycemia, 3 with diabetes insipidus, and 1 with microgenitalia. All 5 with eye signs presented with decreased vision in infancy. The infant with microcephaly underwent a CT scan which demonstrated an absent SP and corpus callosum. The disorder did not appear to be heritable in any case, although there was a female preponderance (12 female, 5 male); 6 of 17 mothers were teenagers at conception. Pituitary hormone deficiencies and CT scan findings are shown below:(*Only 2 patients have reached adolescence)This experience demonstrates the need for an awareness of eye problems in neonates with HP and of HP in infants with optic nerve dysplasia. Whether this clinical triad represents one entity or several remains to be seen.