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 the crinecerfont group and 34 to the placebo group; 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 per liter). At week 4, the androstenedione level was substantially reduced in the crinecerfont group (-197 ng per deciliter [-6.9 nmol per liter]) but increased in the placebo group (71 ng per deciliter [2.5 nmol per liter]) (least-squares mean difference, -268 ng per deciliter [-9.3 nmol per liter]; P<0.001); the observed mean androstenedione value, obtained before the morning glucocorticoid dose, was 208 ng per deciliter (7.3 nmol per liter) in the crinecerfont group, as compared with 545 ng per deciliter (19.0 nmol per 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 (least-squares mean difference, -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.).

Crinecerfont, a CRF1 Receptor Antagonist, Lowers Adrenal Androgens in Adolescents With Congenital Adrenal Hyperplasia.

CONTEXT: Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a rare autosomal recessive disorder characterized by cortisol deficiency and androgen excess due to elevated adrenocorticotropin. OBJECTIVE: To evaluate the safety, tolerability, and efficacy of crinecerfont in adolescents with 21OHD CAH. METHODS: This was an open-label, phase 2 study (NCT04045145) at 4 centers in the United States. Participants were males and females, 14 to 17 years of age, with classic 21OHD CAH. Crinecerfont was administered orally (50 mg twice daily) for 14 consecutive days with morning and evening meals. The main outcomes were change from baseline to day 14 in circulating concentrations of ACTH, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone. RESULTS: 8 participants (3 males, 5 females) were enrolled; median age was 15 years and 88% were Caucasian/White. After 14 days of crinecerfont, median percent reductions from baseline to day 14 were as follows: ACTH, -57%; 17OHP, -69%; and androstenedione, -58%. In female participants, 60% (3/5) had ≥50% reduction from baseline in testosterone. CONCLUSION: Adolescents with classic 21OHD CAH had substantial reductions in adrenal androgens and androgen precursors after 14 days of oral crinecerfont administration. These results are consistent with a study of crinecerfont in adults with classic 21OHD CAH.

Evidence of feedback regulation of C-type natriuretic peptide during Vosoritide therapy in Achondroplasia.

Evidence from genetic disorders of CNP signalling suggests that plasma concentrations of CNP are subject to feedback regulation. In subjects with Achondroplasia (Ach), CNP intracellular activity is suppressed and plasma concentrations are raised but the therapeutic impact of exogenous CNP agonists on endogenous CNP is unknown. In this exploratory dose finding and extension study of 28 Ach children receiving Vosoritide over a 5 year period of treatment, endogenous CNP production was assessed using measurements of plasma aminoterminal proCNP (NTproCNP) adjusted for age and sex and normalised as standard deviation score (SDS), and then related to skeletal growth. Before treatment NTproCNP SDS was raised. Within the first 3 months of accelerating growth, levels were significantly reduced. Across the 5 years of sustained growth, levels varied widely and were markedly increased in some subjects during adolescence. Plasma NTproCNP was suppressed at 4 h post-injection in proportion to the prevailing level of hormone resistance as reflected by SDS before injection. We conclude CNP remains subject to regulation during growth promoting doses of Vosoritide. Fall in CNP during accelerating growth is consistent with an indirect feedback whereas the fall at 4 h is likely to be a direct effect from removal of intra cellular CNP resistance.

C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia.

BACKGROUND: Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification. METHODS: In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 µg per kilogram of body weight (8 patients in cohort 1), 7.5 µg per kilogram (8 patients in cohort 2), 15.0 µg per kilogram (10 patients in cohort 3), or 30.0 µg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 µg per kilogram and then to 15.0 µg per kilogram, and in cohort 2, the dose was increased to 15.0 µg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months. RESULTS: During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 µg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 µg per kilogram for up to 42 months. CONCLUSIONS: In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.).

Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 9 affected individuals.

PURPOSE: Describe the clinical and molecular findings of patients with Kabuki syndrome (KS) who present with hypoglycemia due to congenital hyperinsulinism (HI), and assess the incidence of KS in patients with HI. METHODS: We documented the clinical features and molecular diagnoses of 9 infants with persistent HI and KS via a combination of sequencing and copy-number profiling methodologies. Subsequently, we retrospectively evaluated 100 infants with HI lacking a genetic diagnosis, for causative variants in KS genes. RESULTS: Molecular diagnoses of KS were established by identification of pathogenic variants in KMT2D (n = 5) and KDM6A (n = 4). Among the 100 infants with HI of unknown genetic etiology, a KS diagnosis was uncovered in one patient. CONCLUSIONS: The incidence of HI among patients with KS may be higher than previously reported, and KS may account for as much as 1% of patients diagnosed with HI. As the recognition of dysmorphic features associated with KS is challenging in the neonatal period, we propose KS should be considered in the differential diagnosis of HI. Since HI in patients with KS is well managed medically, a timely recognition of hyperinsulinemic episodes will improve outcomes, and prevent aggravation of the preexisting mild to moderate intellectual disability in KS.

Correction: "Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 10 affected individuals".

The author Diva D. De Leon was incorrectly listed as instead of Diva D. De Leó-Critchlow in the original version of this paper.

Infantile Growth Hormone Deficiency and X- Linked Adrenal Hypoplasia Congenita.

CONTEXT: X-linked adrenal hypoplasia congenita (AHC) is a rare but important cause of primary adrenal insufficiency and can be associated with significant morbidity and mortality. AHC is caused by mutations within the NROB1 gene that codes for the DAX-1 protein, an orphan nuclear receptor essential for the development of the hypothalamic-pituitary-adrenal axis. Affected individuals typically present in early infancy with adrenal insufficiency and growth is usually normal once medical therapy is instituted. Here we report the first case of growth hormone deficiency in an infant with AHC and a novel NROB1 missense mutation. CASE: A two-week old infant presented with salt-losing adrenal crises and a normal newborn screen. Tests of adrenal function confirmed adrenal hypoplasia congenita and molecular evaluation revealed a novel missense NROB1 mutation. Replacement steroid therapy was promptly initiated, but he subsequently developed growth failure despite optimal nutritional and medical steroid therapy. Further biochemical analyses confirmed isolated idiopathic growth hormone deficiency. CONCLUSIONS: Growth failure in adequately treated infants with adrenal hypoplasia congenita is rare and the role of DAX-1 in the development of pituitary somatotropes is not known. There is variable genotype-phenotype correlation in X-linked adrenal hypoplasia congenita but novel NROB1 missense mutations could offer insight into the function of the various DAX-1 ligand-binding domains.

Activation of cyclic AMP signaling leads to different pathway alterations in lesions of the adrenal cortex caused by germline PRKAR1A defects versus those due to somatic GNAS mutations.

CONTEXT: The overwhelming majority of benign lesions of the adrenal cortex leading to Cushing syndrome are linked to one or another abnormality of the cAMP or protein kinase pathway. PRKAR1A-inactivating mutations are responsible for primary pigmented nodular adrenocortical disease, whereas somatic GNAS activating mutations cause macronodular disease in the context of McCune-Albright syndrome, ACTH-independent macronodular hyperplasia, and, rarely, cortisol-producing adenomas. OBJECTIVE AND DESIGN: The whole-genome expression profile (WGEP) of normal (pooled) adrenals, PRKAR1A- (3) and GNAS-mutant (3) was studied. Quantitative RT-PCR and Western blot were used to validate WGEP findings. RESULTS: MAPK and p53 signaling pathways were highly overexpressed in all lesions against normal tissue. GNAS-mutant tissues were significantly enriched for extracellular matrix receptor interaction and focal adhesion pathways when compared with PRKAR1A-mutant (fold enrichment 3.5, P < 0.0001 and 2.1, P < 0.002, respectively). NFKB, NFKBIA, and TNFRSF1A were higher in GNAS-mutant tumors (P < 0.05). Genes related to the Wnt signaling pathway (CCND1, CTNNB1, LEF1, LRP5, WISP1, and WNT3) were overexpressed in PRKAR1A-mutant lesions. CONCLUSION: WGEP analysis revealed that not all cAMP activation is the same: adrenal lesions harboring PRKAR1A or GNAS mutations share the downstream activation of certain oncogenic signals (such as MAPK and some cell cycle genes) but differ substantially in their effects on others.

Total parenteral nutrition associated with severe insulin resistance following hematopoietic stem cell transplantation in patients with hemophagocytic syndrome: report on two cases.

Hyperglycemia secondary to total parenteral nutrition (TPN) is reported in adults. In addition, insulin resistance and type 2 diabetes as late consequences of hematopoietic stem cell transplantation (HSCT) are well described. Both situations are generally manageable with traditional insulin dosing. We present two children who developed severe insulin resistance requiring intravenous insulin therapy at doses up to 13 units/kg/h. Both children were on TPN after undergoing HSCT for hemophagocytic syndrome. We believe that our report will alert physicians to such a condition and help with early recognition that is a key to successful intervention. These cases aim to increase awareness and stimulate research to unravel the associated underling mechanisms.

The nuclear orphan receptor COUP-TFII plays an essential role in adipogenesis, glucose homeostasis, and energy metabolism.

Adipose tissue development and function play a central role in the pathogenesis and pathophysiology of metabolic syndromes. Here, we show that chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) plays a pivotal role in adipogenesis and energy homeostasis. COUP-TFII is expressed in the early stages of white adipocyte development. COUP-TFII heterozygous mice (COUP-TFII(+/-)) have much less white adipose tissue (WAT) than wild-type mice (COUP-TFII(+/+)). COUP-TFII(+/-) mice display a decreased expression of key regulators for WAT development. Knockdown COUP-TFII in 3T3-L1 cells resulted in an increased expression of Wnt10b, while chromatin immunoprecipitation analysis revealed that Wnt10b is a direct target of COUP-TFII. Moreover, COUP-TFII(+/-) mice have increased mitochondrial biogenesis in WAT, and COUP-TFII(+/-) mice have improved glucose homeostasis and increased energy expenditure. Thus, COUP-TFII regulates adipogenesis by regulating the key molecules in adipocyte development and can serve as a target for regulating energy metabolism.

Understanding and interpreting laboratory test results in the clinical management of diabetes mellitus.

The clinical chemistry of diabetes care is unique in Endocrinology, because many of the commonly performed tests, such as assays for glucose, ketones and hemoglobin A1c, are done by the patient at home or by the nurse at the bedside or clinic. Hence, some may assume that these tests are accurate and precise. However, measurement of these substances is often problematic. While laboratory-based glucose analyzers are generally accurate, pre-analytic variables may introduce confusion. Hand held glucose meters are in widespread use and a number of variables are assumed regarding their use, such as hematocrit, oxygen tension and pH. Urine ketone assays may be confusing during conditions altering the mitochondrial redox potential and they are prone to interference from medications. Many different assays for HbA1c are in use today and the various assay types may each be prone to interference from abnormal hemoglobins, iron deficiency states and medication use. International efforts are underway to standardize HbA1c measurements. Insulin assays are being more commonly used as the prevalence of type 2 diabetes and the metabolic syndrome increases. Unfortunately, insulin assays are not standardized, making comparisons of results from different laboratories difficult. Finally, the assessment of diabetes-associated autoantibodies is becoming clinically useful as our understanding of the immunologic basis of diabetes develops and as protocols for the prediction (and ultimately prevention) of the disease arise. While a physician's clinical sense should always guide the interpretation of laboratory values, an understanding of the basis of commonly ordered clinical tests is critical in the care of patients with diabetes.

Variable presentation of precocious puberty associated with the D564G mutation of the LHCGR gene in children with testotoxicosis.

We report on a family with familial male-limited precocious puberty (FMPP) due to a D564G mutation of the LHCGR gene. Family members show a varied phenotypic expression from severe precocity unresponsive to therapy with compromise of the predicted final height in some members, to attainment of tall final stature in other members who never received medical treatment. DNA amplification and sequencing of exon 11 of the LHCGR gene was done for the three affected male members and their mother. DNA analysis revealed a D564G mutation in the third cytoplasmic loop of the LHCGR receptor. All three males had precocious puberty with elevated testosterone levels. The index case developed central precocious puberty and evidence of compromised final height while on therapy. In contrast, the untreated older siblings attained a tall final height. This report underscores the possibility that the effects of the mutant luteinizing hormone/choriogonadotropin receptor on phenotypic expression of FMPP, such as adult final height, are modified by other factors.

Newer therapeutic options for children with diabetes mellitus: theoretical and practical considerations.

Recent studies in adult patients with type 1 diabetes mellitus (T1DM) and T2DM have examined the potential utility, benefits, and side effects of agents that augment insulin secretion after oral ingestion of nutrients in comparison with intravenous nutrient delivery, the so-called incretins. Two families of incretin-like substances are now approved for use in adults. Glucagon-like peptide-1 (GLP-1) or agents that bind to its receptor (exenatide, Byetta) or agents that inhibit its destruction [dipeptidyl peptidase-IV (DPP-IV) inhibitors, Vildagliptin] improve insulin secretion, delay gastric emptying, and suppress glucagon secretion while decreasing food intake without increasing hypoglycemia. Pramlintide, a synthetic amylin analog, also decreases glucagon secretion and delays gastric emptying, improves hemoglobin A1c (HbA1C), and facilitates weight reduction without causing hypoglycemia. We review the historical discovery of these agents, their physiology [corrected] and their current applications. Remarkably, only one or two studies have been reported in children. Pediatricians caring for children with T1DM and T2DM should become familiar with these agents and investigate their applicability, as they seem likely to enhance our therapeutic armamentarium to treat children with diabetes mellitus.

Congenital hypothyroidism in association with Caroli's disease and autosomal recessive polycystic kidney disease: patient report.

Autosomal recessive polycystic kidney disease (ARPKD) is an important renal disease of childhood. Congenital hypothyroidism has been associated with glomerulocystic kidney disease, but to date no association has been made with ARPKD. To our knowledge this is the first reported case of congenital hypothyroidism in an infant with ARPKD.

Neonatal diabetes mellitus: patient reports and review of current knowledge and clinical practice.

Neonatal diabetes mellitus (NDM) is a rare disease reported to have an incidence of one in 400,000 to 500,000 live births. The disorder may be more common as it is not routinely considered a diagnostic possibility by many neonatologists who may routinely use insulin to treat neonatal hyperglycemia. NDM can be grouped into two distinct clinical entities--transient and permanent--based on certain features detailed herein; however, distinction between the two categories can only be definitely made in hindsight. Treatment is with insulin; however, determining the correct dose and method of delivery is often challenging, given the sensitivity of neonates to insulin and the risk of hypoglycemia. We report the successful use of Glargine insulin in the treatment of three infants with NDM, review the recent discoveries, and discuss guidelines for the care of newborns with NDM.

Insulin pump therapy in preschool children with type 1 diabetes mellitus improves glycemic control and decreases glucose excursions and the risk of hypoglycemia.

BACKGROUND: Hypoglycemia in preschool children limits the effectiveness of insulin therapy. Continuous subcutaneous insulin infusion (CSII) is not widely used in this group. OBJECTIVES: This study was designed (1) to test the hypothesis that compared with twice-daily insulin injection, CSII decreases the SD of the mean daily blood glucose (BG) and improves glycemic control and (2) to evaluate the effect of CSII on parental anxiety using the Parental Stress Index (PSI) scale. METHODS: Ten subjects <6 years of age and receiving insulin injections were recruited. Each underwent two 72-h CGMS (Medtronic Minimed, Northridge, CA) monitoring periods and then was started on CSII and re-monitored 3 and 6 months later. We assessed the effects of CSII on the mean BG and SD of BG values, A1c, PSI scores, and number, distribution, and duration of hypoglycemic episodes. RESULTS: Pooled pre- and post-CSII data were compared. There was a 22% decrease in the BG variability (mean +/- SD 93 +/- 19 mg/dL vs. 72 +/- 5 mg/dL; P = 0.02) and a 13% decrease in A1c (8.6 +/- 0.8% vs. 7.5 +/- 0.7%; P = 0.01). There was a decrease in the 24-h median number and duration of hypoglycemic episodes [1.16 vs. 0 episodes/24 h (P = 0.01) and 1.19 vs. 0.05 h/24 h (P = 0.01), respectively], as well as the median number and duration of nighttime episodes [0.83 vs. 0 episode/night (P = 0.008) and 0.98 vs. 0 h/night (P = 0.008), respectively]. We found no statistically significant change in the PSI score. CONCLUSIONS: CSII in preschool children is feasible and safe. Pump therapy reduced the glycemic excursions and decreased hypoglycemia duration and frequency.

Continuous glucose monitoring and the reality of metabolic control in preschool children with type 1 diabetes.

OBJECTIVE: To determine using the MiniMed continuous glucose monitoring system (CGMS) 1) whether twice-daily insulin injection therapy achieves adequate control in preschool children with type 1 diabetes and 2) whether the CGMS is more informative than self-monitoring of blood glucose (SMBG) regarding glucose control and well tolerated by preschool children and their families. RESEARCH DESIGN AND METHODS: Ten children <6 years of age with type 1 diabetes were monitored twice using the CGMS. The distribution of glucose values was analyzed, particularly the frequency, duration, and distribution of hypoglycemia. We analyzed the accuracy of the CGMS in detecting hypoglycemia as well as the clinical relevance of the difference between CGMS and SMBG values. RESULTS: Although hypoglycemia was more frequent during the night (0.8 nighttime episodes . subject(-1) . 24 h(-1) vs. 0.3 daytime episodes . subject(-1) . 24 h(-1)), the difference did not reach statistical significance (P=0.07). However, nighttime episodes lasted longer than daytime episodes (1.2 vs. 0.2 h . subject(-1) . 24 h(-1), P=0.006). Hypoglycemia accounted for 7% and normoglycemia for 24%, while hyperglycemia occurred 64% of the time, with postprandial hyperglycemia being an almost universal feature (94 +/- 7% of all postmeal values). The CGMS correlated well with SMBG without significant clinical discrepancy. The CGMS sensitivity to detect hypoglycemia was 70% with a specificity of 99%; however, the CGMS detected twice as many total episodes as SMBG (82 vs. 40). CONCLUSIONS: Twice-daily insulin injection rarely achieves control in preschool children with type 1 diabetes. The CGMS is well tolerated by patients and has the advantage of revealing daily glucose trends missed by SMBG.