Behavioral effects of prenatal versus postnatal androgen excess in children with 21-hydroxylase-deficient congenital adrenal hyperplasia.

Systematic behavioral studies show that females with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) are masculinized and defeminized in several ways; compared to their sisters, they play more with boys' toys, are more likely to use aggression when provoked, and show less interest in infants. We studied the extent to which these behavioral changes could be attributed to high levels of androgens in the prenatal vs. postnatal periods in 23 girls with CAH, aged 3-12 yr. Sex-atypical behavior was significantly associated with degree of inferred prenatal, but not postnatal, androgen excess; marked boy-typical play was associated with severe salt-wasting CAH, early age at diagnosis, and moderate genital masculinization at birth, but not with bone age advance, concurrent or cumulative high levels of 17-hydroxyprogesterone, or accelerated growth velocity in early childhood. Aggression and interest in infants were not consistently associated with indicators of prenatal or postnatal androgen excess, probably because those behaviors were measured less reliably than was toy play. The results are consistent with the idea that behavioral masculinization in girls with CAH results from high levels of androgens during fetal development and not in postnatal life.

Long-term treatment with GHRH [1-44] amide in prepubertal children with classical growth hormone deficiency.

A cohort of 20 GH deficient prepubertal patients were treated with GHRH [1-44] 10 micrograms/kg or 20 micrograms/kg twice daily for up to four years (5 patients). GHRH treatment resulted in sustained improvement in height velocity. The mean prepubertal height velocity was 3.57 +/- 1.05 cm/yr pretreatment; 8.49 +/- 1.45 cm/yr at year 1; 6.86 +/- 1.45 cm/yr at year 2; 6.22 +/- 0.74 cm/yr at year 3; and 6.16 +/- 0.97 cm/yr at year 4. IGF-I levels increased and remained within normal range. The difference between the children's and the parents' Ht SD scores significantly diminished from a pretreatment difference of -2.43 to -0.48 after four years of treatment. No adverse effects were noted during treatment. We conclude that twice-daily GHRH [1-44] treatment in a small group of prepubertal GH deficient children resulted in sustained improvement in height and growth velocity, and achieved height SDS approaching closely those of their parents.

Identification and assessment of the slowly growing child.

Reliable measurements taken by trained personnel using appropriate equipment are essential in assessment of the slowly growing child. Linear growth plotted on appropriate statistical charts and expected growth based on parental heights are indicators of inappropriately reduced linear growth. Children older than three years of age who grow less than 1.75 in (4.5 cm) per year should be evaluated. Family and personal medical history (including prenatal and birth information) are important in the identification of familial short stature, constitutional delay and other causes of proportionate growth disorders. Other conditions, including chromosomal disorder, systemic disease and endocrine dysfunction, may be discovered during physical examination or appropriate laboratory investigation. Disproportionate growth of the limbs and trunk suggests the presence of a bone or collagen disorder. Bone age data based on radiographs of the left hand may assist in predicting the child's final height.

Low intelligence but not attention deficit hyperactivity disorder is associated with resistance to thyroid hormone caused by mutation R316H in the thyroid hormone receptor beta gene.

Resistance to thyroid hormone (RTH) is a syndrome of reduced responsiveness of tissues to thyroid hormone. The clinical manifestations are variable and 46-50% of children with RTH have attention deficit hyperactivity disorder (ADD). We present a new family with RTH (F120) found to have a mutation R316H in the thyroid hormone receptor beta (TR beta) gene identical for that reported in an unrelated family. Assignment of the mutant allele and haplotyping based on CA repeat polymorphism were done on 16 family members. Semistructured diagnostic interviews and psychometric testing were used to determine the psychiatric diagnosis of 12 family members by examiners blinded to the genotype. Three subjects were identified to have the R316H allele as well as mildly elevated free T4 index (168 +/- 12; normal range 77-135) and nonsuppressed TSH (4.1 +/- 1.7 mU/L). Only 2 of the subjects with RTH were found to have ADD, while one family member homozygous for the wild type TR beta and normal thyroid function tests also had ADD. Unaffected family members had higher full scale intelligence quotients (IQ) (93 +/- 7) than any of the 3 family members with RTH (77 +/- 5, p = 0.006). These data do not support the genetic linkage of ADD and RTH, but do suggest that RTH is associated with lower IQ scores that may confer a high likelihood of exhibiting ADD symptoms.

Subcutaneous growth hormone-releasing hormone therapy in growth hormone-deficient children: first year of therapy.

The purpose of this study was to determine the efficacy and safety of GH-releasing Hormone [GHRH-(1-44)] therapy in GH-deficient children. Twenty previously untreated prepubertal children with GHRH deficiency were treated for 1 yr in a multicenter, open label, company-sponsored study with at least 20 micrograms/kg GHRH-(1-44), sc, half at bedtime and half upon awakening. The main effects were enhancement of linear growth, advancement in bone age, and alteration in general blood chemistries and hormonal values. The mean velocity of the entire group increased from 3.6 +/- 1.1 to 8.1 +/- 1.5 cm/yr (P < 10(-4)) at 1 yr of therapy. After 6 months of therapy, 16 were growing at a mean of 9.4 +/- 2.0 cm/yr and were continued on this dose. In 4 patients who were growing at a rate of 5.5 +/- 1.7 cm/yr, the dose was increased to 40 micrograms/kg daily for the second 6 months. The high dose group increased their mean linear growth velocity for the second 6 months while on the higher dose to 7.6 +/- 0.4 cm/yr (P < 10(-2)). This was equal to the mean velocity for the second 6 months of therapy of the 16 subjects who remained on the 20 micrograms/kg daily therapy (7.6 +/- 1.2 cm/yr). Mean advancement of bone age was 1.3 +/- 0.6 yr during the first year of therapy. No adverse changes in general biochemical, hormonal, or pituitary radiographic analyses were noted. No change in fasting glucose or insulin concentrations, or excessive generation of insulin-like growth factor-I concentrations occurred. We conclude that GHRH in a daily dose of 20-40 micrograms/kg for 1 yr was effective in increasing growth velocity in most GHRH-responsive GH-deficient patients. It was well tolerated without side-effects. Glucose intolerance was not noted.

Glycemic control in early IDDM. The Wisconsin Diabetes Registry.

OBJECTIVE: A cohort (n = 277) was followed from diabetes diagnosis to evaluate longitudinal glycemic control, urinary C-peptide levels, and certain features of diabetes self-management. RESEARCH DESIGN AND METHODS: Unselected cases with IDDM, who were less than 30 yr of age, were identified at diagnosis from a 28-county area in Wisconsin. Subjects were asked to submit blood every 4 mo for GHb testing, to report aspects of diabetes self-management every 6 mo, and to collect a 24-h urine specimen 4 mo after diagnosis. RESULTS: In the 1st yr of diabetes, the rate of increase (0.23%/mo) in GHb was significant for the cohort (P less than 0.001) and for almost all age and sex subgroups. In the 2nd yr, there was no significant rate of increase for the cohort as a whole (P greater than 0.10). Adolescent males (10-19 yr of age) had a mean GHb level for year 2 higher than males of other age-groups and higher than female adolescents (P less than 0.001). Adolescent males had a significant rate of increase in GHb for year 2 (P = 0.02), unlike all other age and sex subgroups. Adolescents had higher initial 24-h urine C-peptide levels than children less than 10 yr of age (P less than 0.01). During the 2nd yr of diabetes, the percentage of adolescent males reporting three or more insulin injections/day was lower than any other subgroup. CONCLUSIONS: These data-suggest that glycemic control stabilizes during the 2nd yr of IDDM, except in adolescent males, and that this may be due partly to aspects of self-management.

Glycemic control and peripheral nerve conduction in children and young adults after 5-6 mo of IDDM. Wisconsin Diabetes Registry.

OBJECTIVE: A cohort of people (n = 86) was examined in the first few months after insulin-dependent diabetes mellitus (IDDM) diagnosis to evaluate the effect of hyperglycemia on nerve conduction velocities and latencies. RESEARCH DESIGN AND METHODS: Unselected cases with IDDM, who were 6-29 yr of age, were identified at diagnosis from a large, geographically defined area of southern Wisconsin. Peripheral nerve conduction was measured on a sample from this cohort. RESULTS: Peroneal nerve conduction velocity was significantly inversely related to glycosylated hemoglobin (P less than 0.05, age and height adjusted). All other nerve conduction velocities and latencies (median motor, median sensory, and sural) showed the same tendency, but the associations were not statistically significant. Twenty-four-hour urine C-peptide and duration of diabetes (3-11 mo) were not consistently related to nerve conduction parameters after controlling for age and height. CONCLUSIONS: These findings suggest that as early as 5-6 mo after diabetes diagnosis, and at a time frequently characterized by partial remission of IDDM, hyperglycemia has a role in the acute slowing of nerve conduction velocity. Other factors such as residual endogenous insulin production do not appear to influence these early changes.

Role of height and glycosylated hemoglobin in abnormal nerve conduction in pediatric patients with type I diabetes mellitus after 4-9 yr of disease.

OBJECTIVE: To determine the role of height and glycosylated hemoglobin in abnormal nerve conduction in pediatric patients with insulin-dependent (type I) diabetes mellitus. RESEARCH DESIGN AND METHODS: Sixty-six pediatric patients (aged 6.3-18.2 yr) with a duration of diabetes from 4 to 8.5 yr but free of clinical neuropathy were evaluated for abnormal nerve conduction. RESULTS: Mean HbA1 values for 1 and 2 yr before study were available. Electroneurographic findings were significantly different from control subjects in upper and lower extremities and included all five measured velocities, three sensory latencies, and one amplitude. Stepwise regression analysis identified an adverse effect of height on latency (5 of 6) and of mean HbA1 concentration on decreasing velocity (4 of 5). The data analysis from 52 patients who were restudied and who had a duration of diabetes from 5.3 to 9.6 yr confirmed that all velocity values slowed; one of five values did so significantly. The coefficients associated with mean HbA1 concentration usually increased in both upper- and lower-extremity velocity analyses at the follow-up examination. The change in peroneal motor velocity between the first and last examinations was significantly related to the increasing time interval between examinations. CONCLUSIONS: Prospective evaluation of nerve conduction parameters in pediatric patients with diabetes should include both height (the most significant independent variable in latency analysis) and mean glycemic control (the most consistent variable in velocity analyses) as variables in the assessment of the natural history of evolving peripheral neuropathy.

24-42 month stability of internal blood standards for glycated hemoglobin analysis.

The stability of fresh and out-of-date Blood Bank standards for quality control of glycated hemoglobin testing was extensively documented. Eight blood standards were prepared as aliquots of washed erythrocytes, stored at -70 degrees C, and assayed in duplicate repeatedly for 24 to 42 months. Significant differences over time were noted only occasionally, and exhibited no consistent trend. Ambient room temperature, 'season of the year', and various mini-column lot numbers had no consistent effect on any blood standard values. In conclusion, washed erythrocytes from controls and patients with IDDM can be stored for future analysis for at least 24 months at -70 degrees C. Out-of-date blood from the Blood Bank can be used with equal stability for at least 18 months.

Epidemiology of insulin dependent diabetes before age 20 in Wisconsin, with particular reference to seasonality.

Physicians in the State of Wisconsin were contacted by mail and asked to report all cases of diabetes in patients under 20 yr diagnosed between 1 July 1982 and 30 June 1984 in order to study factors associated with seasonality in insulin-dependent diabetes mellitus (IDDM). Wisconsin's population is fairly homogeneous and is primarily middle socioeconomic class, small-town or rural, and of northern European Caucasian descent. The incidence of IDDM in winter was higher than in summer during the first year of the study, similarly to results of other studies. However, there was no significant winter peak in diagnosis during the second year. When monthly incidence rates from both years were combined, the increased evidence of IDDM in winter vs. summer was evident in males, but not in females. There appeared to be a spike in the number of new cases of IDDM in the first year of the study which was more evident in males. Such a spike is consistent with spikes in the incidence of IDDM occurring about the same time in Europe and in North America. The percentage of patients with antibody titres to Coxsackie virus and mycoplasma pneumoniae diagnosed during the first winter's peak were equal to those in nondiabetic controls. The distributions of HLA DR types of patients diagnosed in winter were no different from diabetics diagnosed in other seasons. The distribution of HLA DR types (5% DR2, 55% DR3, 82% DR4 and 38% DR3DR4) were similar to those of other groups of Caucasian subjects with IDDM. Also similarly to other studies of IDDM, 14% of the patients had thyroid microsomal antibody titers. The results of this study support the previously-advanced idea that winter might precipitate overt carbohydrate intolerance in individuals in whom insulin cell destruction is already well established (Diabetes, 36, 265-268, 1987). If this is true, studies of seasonality in IDDM might not be informative about the causation of IDDM.

Factors associated with brain herniation in the treatment of diabetic ketoacidosis.

To determine factors contributing to life-threatening brain herniation in patients treated for severe diabetic ketoacidosis, we analyzed history, laboratory data, rate and composition of fluid and insulin administration, and time to onset of brain herniation in nine new cases and 33 prior reports. The overall rate of fluid administration was inversely correlated with the time of onset of herniation (r = -0.32, p = 0.04). Only 4 of 40 cases occurred at fluid intakes less than or equal to 4.0 L/m2/day. During treatment, "calculated" serum sodium concentrations fell significantly and were less than 130 mEq/L in 33% of cases at the time of herniation. These data indicate that excessive secretion of vasopressin may exacerbate the brain edema, and that limitation of the rate of fluid administration may be prudent.

Screening programs for congenital hypothyroidism. How can they be improved?

High-sensitivity neonatal hypothyroid screening tests are used throughout the country. Because of low specificity, primary care physicians are faced with an abundance of false-positive results that challenge the interpreting physician with clinical, economic, and medicolegal considerations. We surveyed 154 physicians caring for Wisconsin-born infants with the highest newborn-screen thyrotropin values in a two-year period. Our results indicated that (1) confirmation of thyroid normalcy is often delayed beyond 6 weeks of age; (2) there is wide variation among physicians regarding therapeutic goals if hypothyroidism is confirmed; and (3) physicians prefer autonomy in the management of congenital hypothyroidism. Modifications in hypothyroid screening programs may include confirmatory tests by a central laboratory (that distributes filter paper with all abnormal results), provision of a management decision tree for primary care physicians, and a one-time subsidy for a visit to a pediatric endocrinologist. We suggest that these modifications may improve the long-term outcome of hypothyroid infants identified by the screening program.

Technetium 99m pertechnetate thyroid scintigraphy: congenital hypothyroid screening.

Technetium 99m pertechnetate thyroid scans were performed on 57 infants referred for evaluation of suspected congenital hypothyroidism. Thyroid anatomy may be characterized by four general types, based on the scintigraphic findings: (1) normal size and location; (2) ectopic location; (3) no detectable thyroid activity; (4) normal location with increased size or uptake. There are diverse etiologies of congenital hypothyroidism. Correlation of thyroid scintigraphy with blood T4 and TSH levels allows specific etiological diagnosis in the majority of cases of congenital hypothyroidism.

Technetium thyroid uptake ratios in pediatric Graves disease.

Patients with Graves disease were prospectively followed by means of three 99mtechnetium thyroid uptake ratios. These three ratios were greater than 90% sensitive and specific for the detection of hyperthyroidism in the patient with untreated Graves disease. Twelve of 15 patients experienced prolonged remission after normalization of the ratios. These ratios exhibit significant linear correlation with serum thyroxine and triiodothyronine concentrations (r = 0.4-0.6, P less than 0.01) and are a very sensitive index of medical oversuppression of thyroid function.

Teledyne Sleep Sentry: evaluation in pediatric patients for detection of nocturnal hypoglycemia.

Twenty-four insulin-dependent diabetic pediatric subjects were studied for 1444 nights for detection of nocturnal hypoglycemia with the Teledyne Sleep Sentry (Teledyne Avionics, Charlottesville, Virginia): a wristwatch-like unit that measures absolute changes in skin temperature and decreases in galvanic skin resistance, indicators of hypoglycemia. The device detected 42 of 46 recognized hypoglycemic episodes. One hundred fifty alarms were sounded without evidence of hypoglycemia, probably due to night sweating. Twenty-five percent of the subjects experienced unacceptable cutaneous reactions, presumably due to metallic iontophoresis.

Empty-sella syndrome. Occurrence in childhood.

Primary empty-sella syndrome has been rarely reported in childhood. Substantial visual disturbance was accompanied by minimal endocrine dysfunction in an 8-year-old girl whose only other complaint was headache. This syndrome in children is associated with more dramatic signs and symptoms than have been reported for adults and may be associated with progressive destruction of pituitary reserve.