Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia.

BACKGROUND: Children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require treatment with glucocorticoids, usually at supraphysiologic doses, to address cortisol insufficiency and reduce excess adrenal androgens. However, such treatment confers a predisposition to glucocorticoid-related complications. In 2-week phase 2 trials, patients with CAH who received crinecerfont, a new oral corticotropin-releasing factor type 1 receptor antagonist, had decreases in androstenedione levels. METHODS: In this phase 3, multinational, randomized trial, we assigned pediatric participants with CAH, in a 2:1 ratio, to receive crinecerfont or placebo for 28 weeks. A stable glucocorticoid dose was maintained for 4 weeks, and the dose was then adjusted to a target of 8.0 to 10.0 mg per square meter of body-surface area per day (hydrocortisone dose equivalents), provided that the androstenedione level was controlled (≤120% of the baseline level or within the reference range). The primary efficacy end point was the change in the androstenedione level from baseline to week 4. A key secondary end point was the percent change in the glucocorticoid dose from baseline to week 28 while androstenedione control was maintained. RESULTS: A total of 103 participants underwent randomization, of whom 69 were assigned to crinecerfont and 34 to placebo; 100 (97%) remained in the trial at 28 weeks. At baseline, the mean glucocorticoid dose was 16.4 mg per square meter per day, and the mean androstenedione level was 431 ng per deciliter (15.0 nmol/liter). At week 4, androstenedione was substantially reduced in the crinecerfont group (-197 ng per deciliter [-6.9 nmol/liter]) but increased in the placebo group (71 ng per deciliter [2.5 nmol/liter]) (least-squares mean difference [LSMD], -268 ng per deciliter [-9.3 nmol/liter]; P<0.001); the observed mean androstenedione value, obtained before the morning glucocorticoid dose, was 208 ng per deciliter (7.3 nmol/liter) in the crinecerfont group, as compared with 545 ng per deciliter (19.0 nmol/liter) in the placebo group. At week 28, the mean glucocorticoid dose had decreased (while androstenedione control was maintained) by 18.0% with crinecerfont but increased by 5.6% with placebo (LSMD, -23.5 percentage points; P<0.001). Headache, pyrexia, and vomiting were the most common adverse events. CONCLUSIONS: In this phase 3 trial, crinecerfont was superior to placebo in reducing elevated androstenedione levels in pediatric participants with CAH and was also associated with a decrease in the glucocorticoid dose from supraphysiologic to physiologic levels while androstenedione control was maintained. (Funded by Neurocrine Biosciences; CAHtalyst Pediatric ClinicalTrials.gov number, NCT04806451.).

A novel mutation in the NR3C1 gene associated with reversible glucocorticoid resistance.

OBJECTIVE: Glucocorticoid resistance is a rare endocrine disease caused by variants of the NR3C1 gene encoding the glucocorticoid receptor (GR). We identified a novel heterozygous variant (GRR569Q) in a patient with uncommon reversible glucocorticoid resistance syndrome. METHODS: We performed ex vivo functional characterization of the variant in patient fibroblasts and in vitro through transient transfection in undifferentiated HEK 293T cells to assess transcriptional activity, affinity, and nuclear translocation. We studied the impact of the variant on the tertiary structure of the ligand-binding domain through 3D modeling. RESULTS: The patient presented initially with an adrenal adenoma with mild autonomous cortisol secretion and undetectable adrenocorticotropin hormone (ACTH) levels. Six months after surgery, biological investigations showed elevated cortisol and ACTH (urinary free cortisol 114 µg/24 h, ACTH 10.9 pmol/L) without clinical symptoms, evoking glucocorticoid resistance syndrome. Functional characterization of the GRR569Q showed decreased expression of target genes (in response to 100 nM cortisol: SGK1 control +97% vs patient +20%, P < .0001) and impaired nuclear translocation in patient fibroblasts compared to control. Similar observations were made in transiently transfected cells, but higher cortisol concentrations overcame glucocorticoid resistance. GRR569Q showed lower ligand affinity (Kd GRWT: 1.73 nM vs GRR569Q: 4.61 nM). Tertiary structure modeling suggested a loss of hydrogen bonds between H3 and the H1-H3 loop. CONCLUSION: This is the first description of a reversible glucocorticoid resistance syndrome with effective negative feedback on corticotroph cells regarding increased plasma cortisol concentrations due to the development of mild autonomous cortisol secretion.

Hormone Therapy During Infancy or Early Childhood for Patients with Hypogonadotropic Hypogonadism, Klinefelter or Turner Syndrome: Has the Time Come?

Managing patients unable to produce sex steroids using gonadotropins to mimic minipuberty in hypogonadotropic hypogonadism, or sex steroids in patients with Klinefelter or Turner syndrome, is promising. There is a need to pursue research in this area, with large prospective cohorts and long-term data before these treatments can be routinely considered.

Diagnosis and management of congenital hypopituitarism in children.

Hypopituitarism (or pituitary deficiency) is a rare disease with an estimated prevalence of between 1/16,000 and 1/26,000 individuals, defined by insufficient production of one or several anterior pituitary hormones (growth hormone [GH], thyroid-stimulating hormone [TSH], adrenocorticotropic hormone [ACTH], luteinizing hormone [LH], follicle-stimulating hormone [FSH], prolactin), in association or not with diabetes insipidus (antidiuretic hormone [ADH] deficiency). While in adults hypopituitarism is mostly an acquired disease (tumors, irradiation), in children it is most often a congenital condition, due to abnormal pituitary development. Clinical symptoms vary considerably from isolated to combined deficiencies and between syndromic and non-syndromic forms. Early signs are non-specific but should not be overlooked. Diagnosis is based on a combination of clinical, laboratory (testing of all hormonal axes), imaging (brain magnetic resonance imaging [MRI] with thin slices centered on the hypothalamic-pituitary region), and genetic (next-generation sequencing of genes involved in pituitary development, array-based comparative genomic hybridization, and/or genomic analysis) findings. Early brain MRI is crucial in neonates or in cases of severe hormone deficiency for differential diagnosis and to inform syndrome workup. This article presents recommendations for hormone replacement therapy for each of the respective deficient axes. Lifelong follow-up with an endocrinologist is required, including in adulthood, with multidisciplinary management for patients with syndromic forms or comorbidities. Treatment objectives include alleviating symptoms, preventing comorbidities and acute complications, and optimal social and educational integration.

Consensus statement by the French Society of Endocrinology (SFE) and French Society of Pediatric Endocrinology & Diabetology (SFEDP) for the diagnosis of Cushing's syndrome: Genetics of Cushing's syndrome.

Cushing's syndrome is due to overproduction of cortisol, leading to abnormal and prolonged exposure to cortisol. The most common etiology is Cushing disease, while adrenal causes are rarer. Knowledge of the genetics of Cushing's syndrome, and particularly the adrenal causes, has improved considerably over the last 10 years, thanks in particular to technical advances in high-throughput sequencing. The present study, by a group of experts from the French Society of Endocrinology and the French Society of Pediatric Endocrinology and Diabetology, reviewed the literature on germline genetic alterations leading to a predisposition to develop Cushing's syndrome. The review led to a consensus statement on genetic screening for Cushing disease and adrenal Cushing's syndrome.