Nancy J. Hopwood

Partial growth-hormone insensitivity: the role of growth-hormone receptor mutations in idiopathic short stature.

Mutations in the GHR locus may play a role in the cause of idiopathic short stature (ISS) by impairing growth-hormone (GH) receptor (GHR) function. At one extreme, mutations that nullify the function of the GH receptor are linked to complete GH insensitivity syndrome, or Laron syndrome, and we hypothesized that less-disruptive mutations could contribute to partial GH insensitivity syndrome. Low levels of GH binding protein may indicate mutations in the extracellular domain of the receptor, and by focusing on 14 children with ISS who had low GH binding protein and insulin-like growth factor I levels, we found three heterozygotes and one compound heterozygote for mutations in the extracellular domain of the receptor. We have since extended our study to a broader spectrum of patients, adding 76 patients with ISS who were treated with GH in a phase II study of the safety and efficacy of recombinant human GH in ISS and also adding 10 patients who were ascertained as having ISS by pediatric endocrinologists in private practice. The GHR gene has thus been analyzed in 100 patients with ISS, eight of whom were found to carry mutations: four in our original study and four with normal or elevated levels of GH binding protein. The latter group consists of three carriers of heterozygous extracellular domain mutations and one carrier of a heterozygous intracellular domain mutation. Family data suggest that the carriers of these mutations have a range of phenotypes, supporting our hypothesis that the expression of these heterozygous mutations as partial GH insensitivity syndrome depends on the genetic makeup of the person.

Growth response of children with non-growth-hormone deficiency and marked short stature during three years of growth hormone therapy

Short-term administration of human growth hormone to children with idiopathic short stature can improve mean growth rate and predicted adult height. It is yet unknown whether therapy would alter pubertal development or affect final height. Three-year treatment results in a group of children with idiopathic short stature are reported. For year 1 of the study, 121 prepubertal children were randomly selected to receive somatotropin, 0.3 mg/kg per week, administered subcutaneously three times weekly (n = 63), or to be nontreatment control subjects (n = 58). After 1 year, all subjects were again randomly selected to receive either three-times-weekly or daily dosing at the same total dose. For the 92 subjects who completed 36 months of treatment, mean growth rate increased from a mean of 4.6 cm/yr before treatment to a mean of 8.0 cm/yr in the first year of treatment. Daily dosing resulted in a significantly faster mean growth rate (9.0 cm/yr) than three-times-weekly dosing (7.8 cm/yr) (p = 0.0005). Mean growth rates were 7.6 and 7.2 cm/yr during years 2 and 3, respectively, and did not differ by dosing group. Mean standardized height for all subjects improved from -2.7 to -1.6 after 3 years. When the growth rate was standardized for bone age, however, subjects who remained prepubertal had a significantly greater gain in mean height SD score than subjects who became pubertal during that 3-year period (p < 0.02). Mean standardized Bayley-Pinneau predicted adult height SD score increased from -2.7 to -1.6 and was independent of the timing of pubertal onset, but for individuals this score was more variable. Year-1 growth response, expressed as growth rate or change in height SD score, was the best predictor of growth in subsequent years. Responses to therapy could not be reliably predicted from baseline anthropometric variables, plasma insulin-like growth factor I SD score, growth hormone levels. Final height assessment will be needed to determine the ultimate benefit of therapy.

Sexual precocity in association with septo-optic dysplasia and hypothalamic hypopituitarism.

Sexual precocity in association with abnormalities of the central nervous system is well known, but its occurrence with hypothalamic hypopituitarism is most unusual. We report five females with septo-optic dysplasia, blindness, and multiple pituitary tropic hormone deficiencies: all were growth hormone and adrenocorticotropic hormone deficient; two had diabetes insipidus; one had sexual precocity, and one had early pubertal maturation, whereas three were prepubertal and responded to administration of synthetic gonadotropin-releasing hormone. These children retained ability to secrete gonadotropins despite the presence of anterior hypothalamic disease. Experimental data from primates plus our observations on these patients raise questions about the role of the anterior hypothalamus in gonadotropin secretion in man.

Neonatal thyroid function in congenital hypothyroidism

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.

Diagnosis of gonadotropin deficiency in adolescents: limited usefulness of a standard gonadotropin-releasing hormone test in obese boys.

The pubertal maturation of five boys (Group A) who were initially thought to be gonadotropin deficient was studied over 10 to 58 months (mean 36 months) by serial physical examinatons and standard GnRH tests. Four were seen because of obesity, delayed sexual maturation, depression, and poor school performance. The other boy had acquired hypothalamic hypopituitarism at 13 years of age. Gonadotropin responses during the initial GnRH test were either absent or abnormally low as related to the degree of skeletal maturation. Subsequent responses showed progressive maturation into the normal range for adult males. These boys had normal olfaction and moderate-to-marked obesity, but initial assessment of testicular size, basal gonadotropins, and testosterone or gonadotropin responses to GnRH did not distinguish these boys from seven patients with isolated gonadotropin deficiency (Group B). Contrary to previous reports and expectations, these studies indicate that an absent or markedly blunted response to synthetic GnRH is not diagnostic of gonadotropin deficiency, even when skeletal age is 12 years or greater. Furthermore, unless a patient is hyposomic or anosmic, or has an associated anomaly such as cleft palate, isolated gonadotropin deficiency cannot be diagnosed reliably until late adolescence or early adulthood.

Thyroid antibodies in children and adolescents with thyroid disorders

Thyroid antibodies were determined by three different techniques in the sera of 125 children and adolescents with thyroid disorders and in the sera of 53 short, normal children without thyroid dysfunction. The incidence of antithyroglobulin antibodies in patients with thyroiditis was highest when measured by radioimmunoassay (85%), less than when measured by hemagglutination (24%), and least by antimicrosomal antibodies (7%). No patient who had initially negative serum for RATA subsequently had positive tests during follow-up of five to 24 months, whereas eight of 31 patients with initially negative serum for ATA later developed positive tests. Treatment appeared to have a suppressive effect on RATA, but not on ATA titers, in hypothroid patients with clinical thyroiditis. The incidence of hypothyroidism in the patients with clinical thyroiditis on initial presentation was significant (37%) and suggests that identification of children and adolescents with thyroiditis is important to ensure adequate medical follow-up.

Acquired hypothyroidismwith muscular hypertrophy and precocious testicular enlargement

PRECOCIOUS sexual matura t ion and muscular hypertrophy are unusual and infrequently reported clinical manifestations of thyroid insufficiency. In 1935, Debrd and Semelaigne 1 emphasized the unusual clinical syndrome of muscular hypertrophy and cretinism which had been described earlier by Kocher. 2 With thyroid therapy the muscular hypertrophy is usually reversible, Precocious testicular enlargement has been reported in 16 hypothyroid male children. 3-6 Four of the children have had an enlarged sella turcica. Increased serum gonadotropins were present in the majority of patients tested. Test icular histology has shown early seminiferous tubular maturation in two cases. The testicular enlargement usually disappears rapidly when the hypothyroid state is corrected. We describe a 9-year-old boy with acquired hypothyroidism and the unique combination of muscular hypertrophy and testicular enlargement.

Growth hormone bioactivity in girls with turner's syndrome: Correlation with insulin-like growth factor I

ABSTRACT: We have recently developed a new bioassay for growth hormone (GH) in serum, which is based on the ability of GH to suppress glucose use in cultured murine adipocytes. We tested the hypothesis that bioactive GH (B-GH) concentrations would correlate better with the GH-dependent peptides, IGF-I, and IGF-binding protein-3 (IGFBP-3) than would GH determined by conventional RIA (RIA-GH). Twenty-five girls with Turners syndrome were studied. The subjects had ages ranging from 4.8 to 15.9 y and height SD from the mean (SD score) ranging from −0.77 to −5.67. Blood samples were obtained every 15 or 20 min for 12 h overnight. For each girl, an equal aliquot of each overnight sample was pooled for determination of B-GH, RIA-GH, IGF-I, IGFBP-3, LH, FSH, and estradiol. Measurable estradiol concentrations were present in six girls and were sufficient to suppress gonad-otropin concentrations in two girls, but they did not alter B-GH, RIA-GH, IGF-I, and IGFBP-3 concentrations compared with the age-matched girls without measurable estradiol concentrations. Hence, data for all girls were combined for subsequent regression analyses. RIA-GH did not correlate significantly with B-GH, IGF-I, or IGFBP-3. B-GH exhibited a significant correlation with IGF-I (r = 0.407, p < 0.05), and the correlation with IGFBP-3 was better than that for RIA-GH (r = 0.355 versus 0.064, B-GH and RIA-GH, respectively). None of the B-GH, RIA-GH, IGF-I, or IGFBP-3 concentrations had a significant correlation with height SD score or height velocity SD score. These results indicate that B-GH correlates better with the GH-dependent peptides, IGF-I and IGFBP-3, than does RIA-GH, but neither measure of GH is useful in predicting height in girls with Turners syndrome.

Nocturnal Serum Growth Hormone Concentration is not Augmented by Short-Term Testosterone Infusion in Pubertal Boys

ABSTRACT: Chronic exposure to testosterone (T) increases growth hormone (GH) secretion. To determine whether acute exposure to T would also enhance GH secretion, we infused saline, followed 1 wk later by T, for 18-24 h at one-third the adult male production rate in 12 pubertal boys and at the adult male production rate in eight additional pubertal boys. Blood was obtained every 20 min for GH and every 30 min for T from 2000-0800 h. Though infusion significantly increased serum T concentrations in all 20 boys, mean GH concentration, GH pulse frequency, and GH pulse amplitude did not increase compared to the saline infusion night. The secretory dynamics of GH as a function of 3-h time blocks from 2000-0800 h were also determined in the eight boys who received the higher dose of T. The profile for mean GH concentration, pulse frequency, pulse amplitude, and peak area were not affected by acute infusion of T at concentrations sufficient to alter LH secretion. This suggests that, at least in pubertal boys, one must be exposed to T for a period longer than 12-18 h to induce increased GH secretion.

62 FAMILIAL PARTIAL PERIPHERAL AND PITUITARY RESISTANCE TO THYROID HORMONE - A FREQUENTLY MISSED DIAGNOSIS?

Two boys, 7 and 9 yrs, and a girl, 11 yrs, presented with goiters and hyperthyroxinemia. The boys were treated with PTU/thyroidectomy or I131 for suspected thyrotoxicosis, but had poorly suppressible serum TSH post Rx. The girl had increasing goiter size on PTU 100 mg q 8 h x 1 mo. These findings led to re-evaluation of thyroid hormone dynamics in these patients and their families. The diagnosis of partial peripheral and pituitary resistance to thyroid hormone was made in the 3 index cases and 12 additional family members, ages 3-38 yrs, compatible with an autosomal dominant inheritance. All had elevated serum T4 RIA (13.9-25.8μg/dl), T3 RIA (205-396 ng/dl), and non-suppressed serum TSH (1.5-158 μU/ml). T3 resin uptakes were N→sl↑. Reverse T3, free T4 and 24h I131 uptakes were ↑ in 6/6. Goiters were present in 10/11 (4 were post thyroid ablation). TRH (200 μg iv) given to 5 pts (from 3 families) showed exaggerated TSH responses (Δ μU/ml = 26, 31, 32, 34, 268). After incremental doses of L-thyroxine up to 0.3 mg/d, goiter size decreased, and TSH response to TRH was now normal (Δ 13,19 μU/ml) in 2 pts with intact thyroids and still exaggerated (Δ 96 μU/ml) in the pt with I131 Rx. Misdiagnosis in 6/15 members of 3 families has led to significant morbidity (hypothyroidism, delayed growth, Rx risk). Appropriate management for this condition should include L-thyroxine in order to decrease goiter size and normalize TSH responses to TRH. A non-suppressed TSH in a patient with suspected thyrotoxicosis should lead to suspicion of this disorder.