Adrenal function in Smith–Lemli–Opitz syndrome

Abstract

Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation syndrome due to mutations of the 7-dehydrocholesterol reductase gene (DHCR7), which leads to a deficiency of cholesterol synthesis and an accumulation of 7-dehydrocholesterol and related metabolites. The SLOS clinical spectrum ranges from multiple major malformations to a mild phenotype with dysmorphic features, intellectual disability and a specific behavioral presentation. Several cases of SLOS with adrenal insufficiency have been described. We performed ovine corticotropin (oCRH) testing in 35 SLOS patients and 16 age- and gender-matched controls. We reviewed prior ACTH stimulation tests of our SLOS patients (19 of 35 available) and reviewed ACTH stimulation tests from additional 10 other SLOS patients. Results from oCRH testing showed that patients with SLOS had significantly higher ACTH baseline values than healthy controls (24.8 ± 15.3 pg/mL vs. 17.8 ± 7.5 pg/mL, p=0.034). However, no statistically significant differences were noted for peak ACTH values (74.4 ± 35.0 pg/mL vs. 64.0 ± 24.9 pg/mL, p=0.303) and for baseline (14.2 ± 7.8 mcg/dL vs. 14.2 ± 6.3 mcg/dL, p=0.992) and peak cortisol values (28.2 ± 7.9 mcg/dL vs. 24.8 ± 8.1 mcg/dL, p=0.156). The area-under-the-curve (AUC) was not significantly different in SLOS patients compared to controls for both ACTH (250.1 ± 118.7 pg/mL vs. 195.3 ± 96.6 pg/mL, p=0.121) as well as cortisol secretion (83.1 ± 26.1 mcg/dL vs. 77.8 ± 25.9 mcg/dL, p=0.499). ACTH stimulation test was normal in 28 of 29 tests. The individual with the abnormal ACTH stimulation test had a normal oCRH test during the same evaluation. The slightly increased baseline ACTH level seen during oCRH testing may be due to compensated mild adrenocortical insufficiency. However, we were able to show that our cohort affected with SLOS had an adequate stress response and that in mild to moderate cases of SLOS stress steroid coverage should not be required.

Treatment of Smith–Lemli–Opitz syndrome and other sterol disorders

“…In spite of near total deficiency of normal bile acids in some patients, fat malabsorption and fat-soluble vitamin deficiencies are rare [Kelley and Hennekam, 2000]. Deficiency of adrenal steroid hormones is also rare in SLOS, and in mild to moderately severe cases of SLOS, the hypothalamic-pituitary-adrenal (HPA) axis functions normally; stress steroid supplementation is not required in these cases [Bianconi et al, 2011]. ACTH stimulation testing and stress steroid dosing for illnesses and other stresses should be considered in severe phenotypes only.…”

Are low maternal estriol levels a predictor for pro‐opiomelanocortin (POMC) deficiency caused by POMC mutation during pregnancy?

“…Fetal pituitary ACTH can be detected by 9 weeks of gestation. Thereafter, the levels of ACTH increase steadily till 20 weeks of gestation . Fetal ACTH regulates steroidogenesis in both adrenal zones.…”

Pulmonary vein stenosis in patients with Smith-Lemli-Opitz syndrome

“…This compound heterozygote combination has been previously described with a severe phenotype. 25,26 The SLOS severity score 24 was in the classical range at 7 (1 point for vermis hypoplasia, 2 for cleft palate, 1 for 2/3 syndactyly, 1 for horseshoe kidney, and 2 for ambiguous genitalia).…”