ANTHROPOMETRIC MEASURES AMONG CHILDREN AND TEENS WITH CLASSIC 46,XX CONGENITAL ADRENAL HYPERPLASIA IN RELATION TO IMPROVEMENTS IN DIAGNOSIS AND CARE.

OBJECTIVES: 1) To examine anthropometric changes of patients with classic 46,XX CAH and matched referents; 2) To investigate the impact of improvements in diagnosis and care on growth patterns in these patients by comparing changes in anthropometric parameters before and after CAH consensus guidelines. METHODS: This was a retrospective cohort study nested within three large integrated health-systems. Seventy-six patients with classic 46XX CAH and 1,102 matched referents <21 years of age were identified. Anthropometric measurements including age-specific percentiles for height, weight, and body mass index were examined and compared between groups using linear mixed-effect models. Anthropometric trajectories were explored using latent class analyses (LCA). RESULTS: CAH patients had lower height percentiles than referents at all time points. Differences ranged from 10.7% to 28.4%. After age 5 differences in height were only significant among study participants born before the publication of CAH consensus guidelines. LCA of height detected a "gradual growth increase" pattern in 28% of CAH cases and only 4% of referents, and a "growth stunting" pattern was observed in 13% of CAH cases and 6% of referents. Height percentile measures did not differ in CAH patients with or without evidence of hormonal interventions (growth hormone and/or puberty blockers) used to increase adult height. CONCLUSIONS: There is substantial heterogeneity in growth trajectories of CAH patients. Although stunting may affect CAH patients, advances in diagnosis and care improved anthropometric outcomes in this population. Understanding the disease- and therapy-related mechanisms that explain the different growth patterns requires additional research.

Fear-potentiated startle response as an endophenotype: Evaluating metrics and methods for genetic applications.

The modulation of the startle response (SR) by threatening stimuli (fear-potentiated startle; FPS) is a proposed endophenotype for disorders of the fearful-fearlessness spectrum. FPS has failed to show evidence of heritability, raising concerns. However, metrics used to index FPS-and, importantly, other conditional phenotypes that are dependent on a baseline-may not be suitable for the approaches used in genetic epidemiology studies. Here, we evaluated multiple metrics of FPS in a population-based sample of preadolescent twins (N = 569 from 320 twin pairs, Mage = 11.4) who completed a fear-conditioning paradigm with airpuff-elicited SR on two occasions (~1 month apart). We applied univariate and multivariate biometric modeling to estimate the heritability of FPS using several proposed standardization procedures. This was extended with data simulations to evaluate biases in heritability estimates of FPS (and similar metrics) under various scenarios. Consistent with previous studies, results indicated moderate test-retest reliability (r = 0.59) and heritability of the overall SR (h2 = 34%) but poor reliability and virtually no unique genetic influences on FPS when considering a raw or standardized differential score that removes baseline SR. Simulations demonstrated that the use of differential scores introduces bias in heritability estimates relative to jointly analyzing baseline SR and FPS in a multivariate model. However, strong dependency of FPS on baseline levels makes unique genetic influences virtually impossible to detect regardless of methodology. These findings indicate that FPS and other conditional phenotypes may not be well suited to serve as endophenotypes unless such codependency can be disentangled.