Context:Patients with congenital adrenal hyperplasia (CAH) often suffer from long-term complications secondary to chronic glucocorticoid therapy and suboptimal treatment regimens.Objective: The aim of the study was to describe clinical characteristics of a large cohort of pediatric and adult CAH patients. Design and Setting:We conducted a cross-sectional study of 244 CAH patients [183 classic, 61 nonclassic (NC)] included in a Natural History Study at the National Institutes of Health. Main Outcome Measure(s):Outcome variables of interest were height SD score, obesity, hypertensive blood pressure (BP), insulin resistance, metabolic syndrome, bone mineral density, hirsutism (females), and testicular adrenal rest (TART). Results:The majority had elevated or suppressed androgens, with varied treatment regimens. Mean adult height SD score was Ϫ1.0 Ϯ 1.1 for classic vs. Ϫ0.4 Ϯ 0.9 for NC patients (P ϭ 0.015). Obesity was present in approximately one third of patients, across phenotypes. Elevated BP was more common in classic than NC patients (P Յ 0.01); pediatric hypertensive BP was associated with suppressed plasma renin activity (P ϭ 0.001). Insulin resistance was common in classic children (27%) and adults (38% classic, 20% NC); 18% of adults had metabolic syndrome. The majority (61%) had low vitamin D; 37% of adults had low bone mineral density. Hirsutism was common (32% classic; 59% NC women). TART was found in classic males (33% boys; 44% men). There is a wide spectrum of phenotypes determined by the residual 21-hydroxylase activity, with a continuum between the classic or severe form and the mild nonclassic (NC) form. The incidence of classic CAH ranges from 1 in 10,000 to 20,000 live births worldwide and is subclassified into salt-wasting (SW) and simple virilizing (SV), re- Conclusions

Extensive genetic analysis beyond targeted CYP21A2 mutational detection is often required to accurately determine genotype in patients with CAH due to the high frequency of complex genetic variation.

In mammals, somatic growth is rapid in early postnatal life but decelerates with age and eventually halts, thus determining the adult body size of the species. This growth deceleration, which reflects declining proliferation, occurs simultaneously in multiple organs yet appears not to be coordinated by a systemic mechanism. We, therefore, hypothesized that growth deceleration results from a growth-limiting genetic program that is common to multiple tissues. Here, we identified a set of 11 imprinted genes that show down-regulation of mRNA expression with age in multiple organs. For these genes, Igf2, H19, Plagl1, Mest, Peg3, Dlk1, Gtl2, Grb10, Ndn, Cdkn1c, and SLC38a4, the declines show a temporal pattern similar to the decline in growth rate. All 11 genes have been implicated in the control of cell proliferation or somatic growth. Thus, our findings suggest that the declining expression of these genes contributes to coordinate growth deceleration in multiple tissues. We next hypothesized that the coordinate decline in expression of these imprinted genes is caused by altered methylation and consequent silencing of the expressed allele. Contrary to this hypothesis, the methylation status of the promoter regions of Mest, Peg3, and Plagl1 did not change with age. Our findings suggest that a set of growth-regulating imprinted genes is expressed at high levels in multiple tissues in early postnatal life, contributing to rapid somatic growth, but that these genes are subsequently downregulated in multiple tissues simultaneously, contributing to coordinate growth deceleration and cessation, thus imposing a fundamental limit on adult body size.