Neural Correlates of Obesity and Inflammation in Children and Adolescents with Congenital Adrenal Hyperplasia.

INTRODUCTION: Patients with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency exhibit an increased prevalence of obesity from childhood including central adiposity and inflammation. There is also an emerging affected brain phenotype in CAH, with decreased cortico-limbic gray matter volumes and white matter abnormalities. We aimed to study the relationship between brain structure, obesity, and inflammation in children and adolescents with CAH compared to controls. METHODS: 27 CAH (12.6±3.4y, 16 females) and 35 controls (13.0±2.8y, 20 females) had MRI of gray matter regions of interest [prefrontal cortex (PFC), amygdala, hippocampus] and white matter microstructure [fornix, stria terminalis (ST)]. Anthropometric measures and lab analytes were obtained. Relaimpo analyses (relative importance for linear regression; percent variance) identified which brain structures were most different between groups. Subsequent regressions further quantified the magnitude and direction of these relationships. Correlations analyzed relationships between brain structure, obesity, and inflammation in the context of CAH status. RESULTS: PFC (13.3% variance) and its superior frontal (SF) subregion (14%) were most different between CAH and controls for gray matter; ST (16%) for white matter. Patients with CAH had lower caudal middle frontal [ß = -0.56, (-0.96, -0.15)] and superior frontal [ß = -0.58 (-0.92, -0.25)] subregion volumes, increased orientation dispersion index in the fornix [ß = 0.56 (0.01, 1.10)] and ST [ß = 0.85 (0.34, 1.36)], and decreased fractional anisotropy in the fornix [ß = -0.91 (-1.42, -0.42)] and ST [ß = -0.83 (-1.34, -0.33)] (all p's <0.05) indicating axonal disorganization, reduced myelin content, and/or higher microglial density within the affected white matter tracts. For the full cohort, SF was correlated with MCP-1 (r=-0.41), visceral adipose tissue (r=-0.25), and waist-to-height ratio (r=-0.27, all p's <0.05); ST was correlated with MCP-1 (r=0.31) and TNF-α (r= 0.29, all p's <0.05); however, after adjusting for CAH status, almost all correlations were attenuated for significance. CONCLUSIONS: Relationships among key brain structures, body composition and inflammatory markers in pediatric patients with CAH could be largely driven by having CAH, with implications for obesity and neuroinflammation in this high-risk population.

Congenital Adrenal Hyperplasia.

We describe congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, which is the most common primary adrenal insufficiency in children and adolescents. In this comprehensive review of CAH, we describe presentations at different life stages depending on disease severity. CAH is characterized by androgen excess secondary to impaired steroidogenesis in the adrenal glands. Diagnosis of CAH is most common during infancy with elevated 17-hydroxyprogesterone levels on the newborn screen in the United States. However, CAH can also present in childhood, with late-onset symptoms such as premature adrenarche, growth acceleration, hirsutism, and irregular menses. The growing child with CAH is treated with hydrocortisone for glucocorticoid replacement, along with increased stress doses for acute illness, trauma, and procedures. Mineralocorticoid and salt replacement may also be necessary. Although 21-hydroxylase deficiency is the most common type of CAH, there are other rare types, such as 11ß-hydroxylase and 3ß-hydroxysteroid dehydrogenase deficiency. In addition, classic CAH is associated with long-term comorbidities, including cardiometabolic risk factors, impaired cognitive function, adrenal rest tumors, and bone health effects. Overall, early identification and treatment of CAH is important for the pediatric patient.

Differences in Hyperandrogenism Related to Early Detection of Non-Classical Congenital Adrenal Hyperplasia on Second Newborn Screen.

Screening for congenital adrenal hyperplasia (CAH) remains heterogenous across geographies-we sought to determine the proportion of non-classical CAH (NCAH) detection by one vs. two newborn screens (NBS) in two U.S. regions. Data were collected at tertiary centers in Houston (HOU) and Los Angeles (LA) on 35 patients with NCAH, comparing patients identified via the NBS vs. during childhood, 17-hydroxyprogesterone (17-OHP) levels, genotype, and phenotype. The NBS filter-paper 17-OHP levels and daily cutoffs were recorded on initial and second screens. In all, 53% of patients with NCAH in the HOU cohort were identified as infants via the second NBS. Patients identified clinically later in childhood presented at a similar age (HOU: n = 9, 5.5 ± 3.1 years; LA: n = 18, 7.9 ± 4 years) with premature pubarche in almost all. Patients in LA had more virilized phenotypes involving clitoromegaly and precocious puberty and were older at treatment onset compared with those identified in HOU by the second NBS (HOU: 3.2 ± 3.9 years; LA: 7.9 ± 4.0 years, p = 0.02). We conclude that the early detection of NCAH could prevent hyperandrogenism and its adverse consequences, with half of the cases in HOU detected via a second NBS. Further studies of genotyping and costs are merited.

Infants with Congenital Adrenal Hyperplasia Exhibit Thalamic Discrepancies in Early Brain Structure.

INTRODUCTION: Patients with classical congenital adrenal hyperplasia (CAH) have prenatal and postnatal hormonal imbalances. To characterize the ontogeny of reported brain and behavior changes in older children with CAH, we aimed to study the brain structure in infants with CAH compared to healthy controls. METHODS: We performed neuroimaging in 16 infants with classical CAH due to 21-hydroxylase deficiency (8 males, gestational age 38.2 ± 1.7 weeks, post-conceptional age [PCA] 42.2 ± 3.0 weeks) and 14 control infants (9 males, gestational age 38.5 ± 1.8 weeks, PCA 42.5 ± 2.4 weeks) utilizing 3-Tesla magnetic resonance imaging. Regional brain volumes were adjusted for PCA and sex, along with an additional adjustment for total brain volume (TBV), for group comparisons by regression analyses (mean, 95% confidence interval [CI]). The degree to which each brain region was differentiated between CAH and control infants was examined by relaimpo analyses, adjusting for all other brain regions, PCA, and sex. RESULTS: Infants with CAH had significantly smaller thalamic volumes (8,606 mm3, 95% CI [8,209, 9,002]) compared to age-matched control infants (9,215 mm3, 95% CI [8,783, 9,647]; ß = -609; p = 0.02) which remained smaller after further adjustment for TBV. Upon further adjustment for TBV, the temporal lobe was larger in infants with CAH (66,817 mm3, CI [65,957, 67,677]) compared to controls (65,616 mm3, CI [64,680, 66,551]; ß = 1,202, p = 0.03). The brain regions most differentiated between CAH versus controls were the thalamus (22%) and parietal lobe (10%). CONCLUSIONS: Infants with CAH exhibit smaller thalamic regions from early life, suggesting a prenatal influence on brain development in CAH. Thalamic emergence at 8-14 weeks makes the region particularly vulnerable to changes in the intrauterine environment, with potential implications for later maturing brain regions. These changes may take time to manifest, meriting longitudinal study through adolescence in CAH.

Weight Loss During Topiramate Treatment in a Severely Obese Adolescent with Congenital Adrenal Hyperplasia and Migraine

Youth with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency exhibit an increased prevalence of obesity, early adiposity rebound, and increased abdominal adiposity compared to unaffected youth. Current obesity management in CAH largely focuses on lifestyle modifications. There is evidence that topiramate therapy is effective in reducing body mass index (BMI), as well as visceral adipose tissue (VAT), in unaffected adolescents with exogenous obesity. However, little is known about the efficacy of topiramate in patients with classical CAH. We report on a 17-year-old female with severe obesity and salt-wasting CAH due to 21-hydroxylase deficiency, who demonstrated reductions in BMI, as well as abdominal visceral and subcutaneous adipose tissue (SAT) while on topiramate therapy. The patient was diagnosed with classical CAH as a newborn with a 17-hydroxyprogesterone 11,000 ng/dL. She had a BMI over the 95th percentile at 3 years of age, followed by unremitting obesity. At 17 years old, she was started on topiramate to treat chronic migraines. Following three years of topiramate therapy, her BMI z-score decreased from +2.6 to +2.1. After four years of therapy, her waist circumference decreased from 110 to 101 cm, abdominal VAT decreased substantially by 34.2%, and abdominal SAT decreased by 25.6%. Topiramate therapy was associated with effective weight loss and reduced central adiposity in an adolescent with classical CAH and severe obesity, without any side effects. Further study is warranted regarding topiramate therapy in obese youth with classical CAH and increased central adiposity, who are at higher risk for significant morbidity.

Components of Metabolic Syndrome in Youth With Classical Congenital Adrenal Hyperplasia.

Classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most common primary adrenal insufficiency in children, involving cortisol deficiency, hyperandrogenism, and cardiometabolic risk. Prior studies have reported that youth with classical CAH have a higher prevalence of the components of metabolic syndrome: obesity, hypertension, elevated fasting blood glucose, and dyslipidemia. Yet, the incidence of the complete metabolic syndrome itself in children and adolescents with CAH is relatively rare. Traditional cardiometabolic risk factors can surface early in children with classical CAH, and continue to present and evolve over the lifetime, although it is only recently that reports of Type 2 diabetes and adverse cardiac events have begun to surface in adults affected by this condition. The pathophysiology underlying the increased prevalence of cardiometabolic risk factors in patients with CAH is not well-understood, with disease treatments and androgen excess having been studied to date. The aim of this review is to evaluate the recent literature on traditional cardiometabolic risk factors in youth with classical CAH, and to consider non-traditional risk factors/biomarkers for subclinical atherosclerosis, inflammation, and insulin resistance. A better understanding of these traditional and non-traditional risk factors in youth with CAH could help guide treatment options and prevent the onset of metabolic syndrome in adulthood, reducing overall patient morbidity.