Congenital micropenis: long-term medical, surgical and psychosexual follow-up of individuals raised male or female.

OBJECTIVES: To document long-term medical, surgical and psychosexual outcome of individuals with congenital micropenis (13 males, 5 females). METHODS: Physical measurements from childhood were collected retrospectively from medical records and at adulthood by physical examination. An adult psychosexual assessment was conducted with a written questionnaire and oral discussion. RESULTS: Adult penile length was below the normal mean in all men. Three women had vaginoplasty resulting in normal length. All men reported good or fair erections but 50% were dissatisfied with their genitalia. Dissatisfaction with body image resulted from having a small penis (66%), inadequate body hair (50%), gynecomastia (33%) and youthful appearance (33%). Ten men were heterosexual, 1 homosexual and 2 bisexual. Among women, 4 (80%) were dissatisfied with their genitalia. Three women reported average libido with orgasm and were also heterosexual. Two women had no sexual interest or experience. Finally, males were masculine and females feminine in their gender-role identity, and both groups were satisfied with their sex of rearing. CONCLUSIONS: Regarding choice of gender, male sex of rearing can result in satisfactory genito-sexual function. Female gender can also result in success, however it requires extensive feminizing surgery.

Autosomal dominant growth hormone (GH) deficiency type II: the Del32-71-GH deletion mutant suppresses secretion of wild-type GH.

Familial isolated GH deficiency type II is an autosomal dominant form of short stature, associated in some families with mutations that result in missplicing to produce del32-71-GH, a protein that cannot fold normally. The mechanism by which this mutant suppresses the secretion of wild-type GH encoded by the normal allele is not known. Coexpression of del32-71-GH with wild-type human GH in transient transfections of the neuroendocrine cell lines GH4C1 and AtT20 suppressed accumulation of wild-type GH. The suppression of wild-type GH accumulation by del32-71-GH was a posttranslational effect on wild-type GH caused by decreased stability, rather than decreased synthesis, of wild-type GH. Coexpression of del32-71-GH with human PRL did not suppress accumulation of PRL, indicating that there was not a general suppression of secretory pathway function. Accumulation of del32-71-GH protein was not necessary for the suppression of wild-type GH, because del32-71-GH did not accumulate in the neuroendocrine cell lines in which suppression of accumulation of wild-type GH was observed. Del32-71-GH did accumulate in transfected COS and CHO cells, but did not suppress the accumulation of wild-type GH in these cells. These studies suggest that del32-71-GH may cause GH deficiency in somatotropes of heterozygotes expressing both wild-type and del32-71-GH by decreasing the intracellular stability of wild-type GH.

Can caretakers of children with IDDM accurately measure small insulin doses and dose changes?

OBJECTIVE: To determine if caretakers of young children with IDDM could consistently reproduce small incremental measurements of insulin (U100). RESEARCH DESIGN AND METHODS: Fifteen caretakers of children with IDDM were asked to deliver repeated small doses of insulin, including doses separated by only 0.25 U of insulin. A sensitive gravimetric technique was used to determine the error in measurement of these low doses of insulin. Statistical analysis was used to evaluate accuracy and internal consistency of each caretaker at each dose. RESULTS: The means +/- SD at each dose level were as follows: 2.75 +/- 0.13 U at 2.5 U, 3.19 +/- 0.13 U at 3.0 U, 3.55 +/- 0.13 U at 3.25 U, and 3.70 +/- 0.11 U at 3.5 U. All doses were biased toward overadministration. There was as statistically significant difference in the dose delivered when the target doses were varied by only 0.25 U. The average differences and standard errors between 2.5 U and 3.0 U, 3.0 U and 3.25 U, and 3.25 U and 3.5 U were 0.44 +/- 0.20 U, 0.36 +/- 0.018 U, and 0.15 +/- 0.017 U, respectively. CONCLUSIONS: Participants were not accurate in measuring small insulin doses, consistently overdrawing insulin by an average of 0.22 U. Caretakers are reasonably internally consistent with a given dose, since participants were able to measure statistically significant differences in 0.25 U dose changes. The error in insulin measurement does not vary with the intended dose level. Caretakers in the same family deliver insulin doses as variable from each other as they are from the population as a whole; however, when two or more individuals are responsible for one insulin dose in a child with IDDM, they have a combined variability that is approximately 40% greater than a single individual's variability.

Accuracy and precision of low-dose insulin administration.

OBJECTIVE: To determine the lowest dose of concentrated (U100) insulin that can be reproducibly delivered. METHODS: A telephone survey was used to determine current practices in major pediatric hospitals regarding the administration of low doses of concentrated insulin. A sensitive gravitometric technique was used to determine the error in measurement of low doses of U100 insulin by pediatric nurses and parents of diabetic children. RESULTS: A telephone survey revealed that doses as low as 0.5 or 1.0 U (5 to 10 microL) are routinely administered in pediatric hospitals. In our study of pediatric nurses, attempts to deliver 0.5, 1.0, and 2.0 U resulted in delivered doses of 0.975 +/- 0.315, 1.638 +/- 0.376, and 2.153 +/- 0.435 U (mean +/- standard deviation of the mean), respectively. The use of 0.3-mL syringes compared to 0.5-mL syringes did not improve accuracy or precision. Taken as a group, parents of children with diabetes were more accurate (mean delivered dose of 1.063 +/- 0.276 for the 1-U dose), but the individual means ranged from 0.641 to 1.300 and coefficients of variation ranged from 5% to 33%. Only three of the seven parents could deliver 1.0 U with acceptable precision and accuracy. CONCLUSIONS: When currently available syringes are used, insulin injections of less than 20 microL (2 U of U100) have an unacceptably large error. It is recommended that, in the inpatient setting, diluted insulin be used if the prescribed dose is less than 2.0 U.

Growth in children after bone marrow transplantation: busulfan plus cyclophosphamide versus cyclophosphamide plus total body irradiation.

Growth was assessed during the first and second years following bone marrow transplantation (BMT) in 47 children treated by either busulfan plus cyclophosphamide (BU/CY) (n = 24) or cyclophosphamide plus fractionated total body irradiation (CY/TBI) (n = 23). Before transplant, the median height was only 0.2 SD below age- and sex-adjusted means (range, -2.5 to +3.0). Height was greater than 2.0 SD below normal in only three patients (6%). The pretransplant heights were comparable in the BU/CY and CY/TBI groups (-0.1 v -0.6 SD, P = .35). Following transplant, median 1- and 2-year heights were 0.7 and 0.9 SD below normal, respectively. Growth rates were 2.2 SD and 1.4 SD below normal during the first and second years, respectively. Growth rates were greater than 2.0 SD below normal in 24 of 47 (51%) at 1 year and in 12 of 31 (39%) at 2 years after transplant. Growth rates in patients treated with BU/CY were comparable to those treated with CY/TBI during both years: -2.5 versus -1.7 SD during the first year (P = .19, Wilcoxon), and -1.5 versus -1.1 SD during the second year (P = .61). Growth rates during the second year correlated with growth rates during the first year (r = .36, P = .046). Growth rates during the first year were lower in patients who had been given prior cranial irradiation, those who were near pubertal age at the time of transplant, and those who were transplanted for a disease other than acute lymphoblastic leukemia (ALL). During the second year, poor rates of growth were associated only with the use of corticosteroids after transplant.

Long-term follow-up of hypopituitary patients treated with human growth hormone.

Thirty-six former human growth hormone (hGH) recipients underwent comprehensive physical, endocrine and lipoprotein evaluations as adults. Treatment was associated with a decrease in height standard deviation score (SDS) in males from 4.0 pretreatment to 2.1 as adults, and in females from 4.2 to 2.5. Males showed a better growth response to treatment than did females. Plasma somatomedin-C levels were subnormal in 30 patients, but were higher in isolated growth-hormone-deficient patients than in others. Three men and 1 woman showed evidence suggesting a disturbance in pulsatile gonadotropin release despite the previous documentation of normal serum gonadotropin levels. Hypertriglyceridemia was not observed, and the women's plasma cholesterol levels were unremarkable. Men, however, showed higher-than-expected total cholesterol, LDL-cholesterol, and HDL-cholesterol concentrations. The last finding may explain the lack of increased cardiovascular morbidity in this group.

Insulin pumps in children with diabetes.

Insulin pump therapy or continuous subcutaneous insulin infusion is becoming more common. Nurses can expect to encounter a growing number of children who have insulin pumps and an increasing number of questions concerning the general application and efficacy of these pumps. Therefore it is important that pediatric nurse practitioners, school nurses, and pediatric nurses understand insulin pump therapy and its role in the overall treatment of children with diabetes. This article describes the advantages, disadvantages, and alternatives to insulin pump therapy. It also discusses staff expertise, patient selection criteria, and patient education as elements of successful insulin pump management.

Academic promotion at a medical school. Experience at Johns Hopkins University School of Medicine.

We studied promotions at Johns Hopkins University School of Medicine to determine whether clinician-teachers are less likely to be promoted or are promoted later in life than researchers and whether those who are promoted have more articles published than those who are not promoted. Over a five-year period, 93 percent of candidates for the rank of associate professor and 79 percent of the candidates for the rank of professor were promoted. There were no significant differences between clinical and research faculty members in terms of the probability that they would be promoted or their age at promotion to either associate professor or professor. Despite these findings, the responses to a questionnaire indicated that former faculty members perceived clinician-teachers as less likely than researchers to be promoted. Those who were promoted had had about twice as many articles published in peer-reviewed journals as those who were not promoted. We recommend improved counseling of medical school faculty members and more extensive discussion of the criteria for promotion and the chances of academic success.

Age-related anti-thyroid antibodies and thyroid abnormalities in Turner syndrome.

One hundred pediatric patients with Turner syndrome were studied to determine the correlation between the presence of anti-thyroid antibodies with age and karyotype, and the value of anti-thyroid antibody titers as predictors of subsequent thyroid abnormalities. (54 patients = 45,X; 46 = other karyotypes.) The frequency of positive titers of anti-thyroid antibodies increased linearly with cumulative age. Anti-parietal cell and anti-adrenocortical cell antibodies were not increased in these patients (1.3 and 2.6% respectively). The ability to use positive anti-thyroid antibody titers to predict the development of thyroid abnormalities increased from age 10 years and became statistically significant at ages 13-17 years for the whole group as well as 45,X patients. None of the patients had clinical symptoms of thyroid dysfunction although 22% developed thyroid abnormalities, which included elevated TSH, low T4, and/or goiter.

The short child. A matter of time or cause for concern?

Short stature is less likely to have an endocrine basis than is commonly thought. Any of a number of chronic systemic diseases can slow growth, short stature may result from a genetic tendency or disorder, growth may be constitutionally delayed, or it may be retarded by intrauterine influences. True endocrine causes include thyroid or adrenal disorder, growth hormone deficiency, and psychosocial dwarfism. Although growth hormone deficiency is quite rare, it has received increased attention recently. The capability to produce human growth hormone by recombinant DNA techniques presents the prospect that replacement therapy will be more readily available to those patients who might benefit from it. Caution is called for, however, in making use of this agent for patients other than those with proven growth hormone deficiency.

Hypertension in neonatal hyperthyroidism.

Hypertension has only recently been reported in neonatal hyperthyroidism. We describe three children with hypertension as a prominent part of the syndrome. Antihypertensive therapy alone was ineffective in controlling elevated BP. All patients showed gradual resolution of hypertension once a euthyroid state was achieved.

Turner syndrome patients with a ring X chromosome.

A patient with clinical features of Turner syndrome and a 45,X karyotype in repeated blood cultures was re-evaluated when she spontaneously entered puberty. A ring X cell line was found in a small proportion of fibroblasts. A review of 35 previously published ring X cases is presented. All are mosaic, the major cell line in most cases being 45,X. There is wide variation in the frequency with which the abnormalities associated with Turner syndrome are found in these patients. All have short stature. Some are sexually developed and fertile. Cardiovascular anomalies are uncommon. This phenotypic variation may have at least two causes: the size of the deleted portion at each end of the X chromosome, and the relative frequency and distribution of 45,X and 46,X,r(X) cell lines in various body tissues.

Human growth hormone treatment of children with growth failure and normal growth hormone levels by immunoassay: lack of correlation with somatomedin generation.

Children with growth failure, normal growth hormone responses to stimulation tests, and low somatomedin levels are being recognized with increasing frequency. Sixteen patients, aged 2 to 17 years, with these findings were studied. When treated with human growth hormone, the mean plasma somatomedin-C levels of these patients increased from 0.19 +/- 0.05 (SD) U/mL to 2.29 +/- 1.11 U/mL (P less than .001) and mean growth velocity increased from 3.6 +/- 1.6 (SD) cm/yr to 7.4 +/- 2.9 cm/yr at 8 months of treatment (P less than .001). The effect of human growth hormone therapy on the whole group was statistically significant, but the effect on individuals was highly variable. There was no correlation between magnitude of the increase in somatomedin-C and growth response (r = .26, NS). Thus, the long-term growth-promoting effect of human growth hormone therapy in this group of patients could not be predicted from the magnitude of the somatomedin-C responses.

Genetic analysis of familial isolated growth hormone deficiency type I.

Nuclear DNA from individuals belonging to nine different families in which two sibs were affected with isolated growth hormone deficiency type I were studied by restriction endonuclease analysis. By using 32P-labeled human growth hormone or the homologous human chorionic somatomammotropin complementary DNA (cDNA) sequences as a probe, the growth hormone genes of affected individuals from all families yielded normal restriction patterns. Polymorphic restriction endonuclease sites (HincII and MspI), which are closely linked to the structural gene for growth hormone on chromosome 17, were used as markers in linkage analysis of DNA of family members. Of the nine affected sib pairs two were concordant, three were possibly concordant, and four were discordant for both linked markers. Since only concordant sib pairs would have inherited the same growth hormone alleles, further studies to identify mutations of the growth hormone genes should be limited to this subgroup. It is unlikely that the discordance observed in four of the sib pairs is due to recombination, because the polymorphic HincII site is only 116 base-pairs from the -26 codon of the growth hormone gene. Thus, in at least four of the nine families, the mutation responsible for isolated growth hormone deficiency is not within or near the structural gene for growth hormone on chromosome 17.

Short term improvement in glycemic control utilizing continuous subcutaneous insulin infusion: the effect on 24-hour integrated concentrations of counterregulatory hormones and plasma lipids in insulin-dependent diabetes mellitus.

Eight patients with established insulin-dependent diabetes mellitus were studied before and 2 weeks after the initiation of pumped continuous sc insulin infusion in order to investigate the effect of short term improvement of glycemic control on hormonal and lipid levels. Glycemic control was improved in all patients. Using a constant blood withdrawal pump, accurate 24-h average concentrations, denoted integrated concentrations, were obtained. The mean 24-h integrated concentrations of GH, cortisol, norepinephrine, and epinephrine did not change significantly. The mean fasting triglyceride concentration dropped from 119.1 to 83.4 mg/dl (P less than 0.05). The mean 24-h integrated concentration of plasma triglycerides fell from 132.1 to 101.5 mg/dl (P less than 0.02). Both mean fasting and mean 24-h integrated concentrations of plasma cholesterol were lower after improved control. Short term improvement in glycemic control was associated with a reduction in plasma lipid concentrations, but failed to alter mean 24-h integrated concentrations of the measured counterregulatory hormones.

Ontogeny of erythrocyte insulin binding in the sheep.

The ontogeny of insulin binding in the sheep was studied using the erythrocytes (RBCs) of 31 fetuses, 10 lambs, and 5 adult animals. Six fetuses were studied on three occasions over a 2-week period from 120--135 days of gestation to provide longitudinal data on changes in insulin binding. Maximal percent binding of [125I]iodoinsulin and receptor concentration decreased significantly as the age of the animal increased (r = 0.76, P less than 0.001 and r = --0.49, P less than 0.001, respectively). Total loss of insulin binding to RBCs was estimated to occur in the second postnatal month, and the RBCs from the adult sheep showed no specific insulin binding. The osmotic fragility of RBCs in each developmental group of animals was also studied to assess possible differences in RBC membrane properties. RBC osmotic fragility was significantly lower in fetuses than in adult sheep (osmotic fragility 50 = 0.55% phosphate-buffered saline vs. 0.76% phosphate-buffered saline, respectively; P less than 0.001). The data suggest that fetal RBCs of lower osmotic fragility and high insulin binding capacity are progressively replaced during late prenatal and early postnatal life by adult-type RBCs of increased osmotic fragility and lacking binding capacity for insulin. The timing of the disappearance of insulin binding to RBCs coincides with the final transition in the animals from a monogastric to a ruminant metabolic state, and may reflect a change in the need for insulin with age.

Erythrocyte insulin binding in insulin-dependent diabetes mellitus: lack of relationship to duration and control of diabetes in children and adolescents.

Insulin binding was measured in the erythrocytes (RBCs) of four children and 12 adolescents with insulin-dependent diabetes mellitus in the basal (fasting, nonketotic) state. Children and adolescents with insulin-dependent diabetes mellitus showed normal binding of insulin to their RBCs when expressed as the total insulin bound over the physiologic range of insulin concentrations. The insulin receptor concentration and receptor binding affinity for insulin were also normal. These parameters of insulin binding were not correlated with either the duration of diabetes or the degree of diabetic control in the patients. Since insulin binding by erythrocytes has been shown to reflect binding by traditional target tissues (liver, fat), the data suggest that alterations in binding of insulin to cells in children and adolescents with insulin-dependent diabetes mellitus probably play little, if any, role in the response of these patients to exogenous insulin or in the control of their glucose metabolism in the basal state.