Nonprogression of subclinical beta-cell dysfunction among first-degree relatives of IDDM patients. 5-yr follow-up of the Seattle Family Study.

It is unknown among first-degree relatives of individuals with insulin-dependent diabetes mellitus (IDDM) whether the disease process occurs in relatively few but always progresses to clinical IDDM or whether subclinical disease is more common but remains nonprogressive in many cases. Islet cell antibodies (ICAs) were found in 21 of 724 (2.9%) first-degree relatives during screening in the greater Seattle area between 1983 and 1988. Measures of beta-cell function (glucose disappearance rate [Kg], fasting insulin, acute insulin response to intravenous arginine [AIRarg], acute insulin response to intravenous glucose [AIRgluc], slope of glucose potentiation of AIRarg) and insulin sensitivity were obtained. Twenty individuals, 9 ICA+ relatives and 11 ICA- relatives, were evaluated prospectively. When expressed in relation to the expected AIRgluc based on each subject's sensitivity index, AIRgluc in 18 of 20 relatives fell below 100%, indicating inappropriately low insulin secretion (subclinical beta-cell dysfunction). After a median follow-up of 42 mo, 10 of 11 ICA- relatives remained ICA-. None showed deteriorating beta-cell dysfunction, and none developed diabetes. Five ICA+ relatives showed persistent immunologic positivity. beta-Cell function remained remarkably stable in all except 2 relatives. One was a 15-yr-old boy who developed IDDM shortly after screening and before evaluation of beta-cell function could be carried out. The other was an 18-yr-old monozygotic twin who developed IDDM after 27 mo. Both of these individuals had ICAs of 80 Juvenile Diabetes Foundation U and had been discordant for less than 5 yr.(ABSTRACT TRUNCATED AT 250 WORDS)

Activity of the stimulatory guanine nucleotide-binding protein is reduced in erythrocytes from patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism: biochemical, endocrine, and genetic analysis of Albright's hereditary osteodystrophy in six kindreds.

Multiple hormone resistance in many patients with pseudohypoparathyroidism (PHP) type Ia and Albright's hereditary osteodystrophy (AHO) is associated with deficient activity of the stimulatory guanine nucleotide-binding protein (Gs) of adenylate cyclase. To study further the relationship of deficient Gs activity to hormone resistance, we evaluated endocrine function and measured Gs activity of erythrocyte membranes from AHO patients with clinical hormone resistance (PHP type Ia) and from family members with AHO alone (pseudopseudohypoparathyroidism). The results of erythrocyte membrane Gs determinations were compared to those of unaffected relatives and normal subjects. Patients with pseudopseudohypoparathyroidism (pseudoPHP) had reductions in erythrocyte membrane Gs activity comparable to those in patients with PHP type Ia [43.4 +/- 11.9% (+/- SD) for PHP type Ia vs. 47.8 +/- 9.5% for pseudoPHP]. However, in contradistinction to patients with PHP type Ia, individuals with pseudoPHP did not have obvious endocrine dysfunction. Although deficient Gs activity appears to play an important role in the pathogenesis of these disorders, it is possible that Gs deficiency must be combined with other factors that limit cAMP production to cause clinically overt endocrine disease.

Growth hormone deficiency following radiation therapy of primary brain tumors in children.

The medical records of 123 patients treated for brain tumors at Children's Hospital and Medical Center, Seattle, Washington, between 1985 and 1987 were reviewed. The endocrinological complications of radiation therapy and the effectiveness of growth hormone (GH) replacement therapy were assessed. These were the first 2 years after synthetic GH became available. The disease pathology was confirmed at craniotomy or biopsy in 108 patients. Ninety-five children completed radiation therapy and 65 of these were alive at the time of review; these 65 children represent the study population. The most common tumor types were medulloblastoma, craniopharyngioma, and ependymoma. Endocrine evaluation was initiated with changes in the patients' growth velocity. Patient workup included skeletal x-ray films for determination of bone and analysis of thyroxin, thyroid-stimulating hormone, and somatomedin-C levels. Following 1-dopa and clonidine stimulation, provocative studies of GH levels were performed. Growth hormone failure and short stature were observed in 26 children, most commonly in the 2nd year after tumor treatment. Eight patients with GH failure were also hypothyroid. Hormone replacement therapy was initiated with recombinant GH, 0.05 mg/kg/day, and all children so treated showed an increase in height, with eight patients experiencing catch-up growth. There were no complications of therapy or tumor recurrence. Studies of baseline bone age and somatomedin-C levels on completion of radiation therapy are recommended. Comprehensive endocrine studies should follow changes in the patients' growth velocity. With early GH replacement, catch-up growth is possible and normal adult heights may be achieved.

Detection of heterozygotes for congenital adrenal hyperplasia: 21-hydroxylase deficiency-a comparison of HLA typing and 17-OH progesterone response to ACTH infusion.

We have studied nine families in which at least one member has congenital adrenal hyperplasia, to compare the predictive value of HLA typing and the 17-hydroxy progesterone response to ACTH as methods for detection of heterozygotes. In each of six families, two children were affected and were HLA genotypically identical. None of the unaffected siblings were HLA identical with their affected siblings. When the 17-OHP response to ACTH and the HLA haplotypes of parents and unaffected siblings were compared, there was a 79% concordance for identification of heterozygotes. Two siblings were carriers according to HLA typing, but had normal 17-OHP responses consistent with the carrier state. Three individuals with recombinations involving the HLA region of chromosome number 6 were detected. Analysis of these recombinant individuals provided additional evidence suggesting that the 21-OH degrees gene is closely associated with the B-locus of HLA. When an affected individual has been identified, HLA typing is a direct and reliable method for determining the carrier state among family members.

Failure to detect genomic viral sequences in pancreatic tissues from two children with acute-onset diabetes mellitus.

Two cases of fatal, acute-onset, insulin-dependent diabetes mellitus (IDDM) in children were diagnosed. Epidemiologic and serologic studies, as well as histologic analysis of pancreatic tissue in fatal viral infections, support the contention that a viral infection could cause beta cell destruction, leading to IDDM. The presence of nucleic acid sequences from viral agents considered to be potentially diabetogenic, specifically, cytomegalovirus and mumps, rubella, and coxsackie viruses, were investigated in the pancreatic tissues by reverse transcription followed by polymerase chain reaction (RT-PCR) and Southern blot hybridization. Total pancreatic RNAs extracted from five children who died from nondiabetic causes were included as controls. Viral genetic information from any of these four viral agents was not found. This result indicates that the acute IDDM in these cases was not due to a direct infection of pancreatic beta cells by any of the viral agents studied.