We have studied ten phenotypically similar patients with complete androgen insensitivity. All of the patients tested had significantly elevated serum luteinizing hormone and plasma androgens within or above the normal adult male range. On the basis of s ecific dihydrotestosterone binding by skin fibroblasts, we identified two subgroups. Six patients from five different families had undetectable dihydrotestosterone binding, while four patients from two families had normal binding activity. Our results indicate that within the clinical syndrome of androgen insensitivity there are at least two distinct genetic variants. These variants may result from allelic mutations of the same X-linked gene specifying the dihydrotestosterone receptor or, alternatively, from mutations of separate genes both being essential for androgen action in responsive cells.Recently we reported the presence of a receptor protein specific for dihydrotestosterone (DHT) in the cytoplasm and nucleus of cultured human skin fibroblasts (1, 2). In contrast, cells from two male siblings with complete androgen insensitivity syndrome (AIS) showed no detectable specific D4T binding (2, 3). The androgen insensitivity in this family apparently resulted from a mutation of an X-linked gene specifying the DHT receptor (3).In order to determine whether other patients with this clinical syndrome demonstrate a similar defect in androgen binding, we have studied additional patients with the AIS phenotype. On the basis of the DHT binding characteristics of their fibroblasts, two distinct groups were identified, those with undetectable DHT binding and those with normal androgen binding activity. These findings suggest that there is genetic heterogeneity among patients with androgen insensitivity. MATERIALS AND METHODSSubjects. Ten subjects with complete AIS were studied. Subjects no. 1 and 2 are nonidentical twins who were previously reported to have absent DHT binding activity in their skin fibroblasts (2). Subject no. 5, described by Wilkins (4), had a similarly affected sibling. Subjects no. 7, 8, and 9 (individuals IV-2, IV-4, and IV-10 in Fig. 1) are from a family described in detail elsewhere (5, 6). The pedigree shown in Fig. 1 has been revised from that previously reported (6). The remaining four subjects were sporadic cases with no family history of similar disorder.All Whole cell DHT binding was measured as previously reported (1, 2). Confluent monolayers of fibroblasts in 100 mm petri dishes were incubated for 20 min at 370 with [3H]DHT (0.2 to 1.5 X 10-9 M) dissolved in minimal essential medium without fetal calf serum. After incubation, the cells were harvested using 0.25% trypsin and washed at 40 in Tris-sucrose buffer (0.02 M Tris-HCl, pH 7.5, 0.32 M sucrose, 1 mM MgCl2) containing 1 mg/ml of bovine gammaglobulin. All subsequent procedures were carried out at 4°. After centrifugation at 800 X g for 15 min, the cells were suspended in 1.0 ml of Tris-KCl buffer (0.02 M Tris-HCl, pH 7.5, 0.5 M KC1, 1.5 mM EDTA) and lysed in an ultrasonic clean...

Background. One in three adolescents and young adults with type 1 diabetes have at least one early diabetes-related complication/comorbidity. However, the prevalence, patterning, and risk factors for co-occurring complications in this population are not well understood. Methods. The SEARCH for Diabetes in Youth observational cohort study includes 1327 individuals diagnosed with type 1 diabetes before 20 years of age from 5 United States locations. Sociodemographic and metabolic risk factors were assessed at baseline (mean diabetes duration = 0·8 years, mean age = 10·9 years) and follow-up (mean diabetes duration = 7.8 years, mean age = 18·0 years). Early diabetes complications (diabetic kidney disease, diabetic retinopathy, peripheral neuropathy, cardiovascular autonomic neuropathy, and arterial stiffness) were assessed at follow-up. We aimed to describe co-occurrence of complications and examine differences in co-occurrence within demographic and metabolic risk factor clusters identified using cluster analysis. Findings. Overall, co-occurrence of any ≥2 complications was observed in 5·9% of all participants, more frequently than expected by chance alone (4·4%, p=0·015). Specifically, retinopathy and diabetic kidney disease, retinopathy and arterial stiffness, and arterial stiffness and cardiac autonomic neuropathy all co-occurred more frequently than expected (all p<0·05). The cluster analysis produced four unique clusters characterized by progressively worsening metabolic risk factor profiles (longer duration; higher A1c, non-HDL cholesterol, and waist to height ratio) and differences in sociodemographic characteristics (race/ethnicity, household income, type of health insurance). Prevalence of ≥2 complications progressively increased with worsening metabolic profiles (from 2·3% to 20·8%, p<0·001). Interpretation. We report that early complications co-occur in adolescents and young adults with type 1 diabetes more frequently than expected after an average of less than eight years of diabetes duration. A cluster of high risk factors identifies groups that may benefit most from interventions to reduce complications.

We investigated eight patients with the Reifenstein syndrome to define the hormonal basis for this condition. The patients had normal or elevated concentrations of plasma androgens, normal production rates of testosterone and dihydrotestosterone, elevated serum levels of luteinizing hormone and normal 5alpha-reductase activity in skin fibroblasts. These findings indicate that the syndrome results from defective androgen action rather than from decreased androgen synthesis. The term "partial androgen insensitivity syndrome" describes this condition more accurately than a term based on clinical phenotype. Dihydrotestosterone binding studies in skin fibroblasts demonstrated two genetic variants similar to those reported in complete androgen insensitivity syndrome. One patient had a partial deficiency of cytoplasmic dihydrotestosterone binding, and four others had normal binding activity. The cause of the androgen insensitivity in the last four cases is unknown. Treatment with testosterone suppressed serum luteinizing hormone levels and promoted mild virilizing effects.

A 15-year-old adolescent male with dissecting aortic aneurysm is presented. His young age, lack of predisposing factors, and fulminant course with rapid progression to death precluded a correct antemortem diagnosis. Review of the literature reveals that most instances of dissecting aortic aneurysm in childhood and adolescence are associated with predisposing conditions, especially congenital cardiovascular anomalies. The clinical picture is generally characteristic. Prompt evaluation and therapy may be lifesaving.